MBD4c.1543+14C>TBenign

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Variant interpretation report

MBD4 c.1543+14C>T, p.?

NM_001276270.2:c.1543+14C>T NP_001263199.1:p.? View identifiers

Classification

Benign

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.

Benign.A benign classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About MBD4

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 stand alone (benign) · 1 strong (benign) · 3 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 3 Benign
Pipeline record: 4 Aug 2026 · version 7.0.5

Evidence considered

View criteria

Applied evidence criteria

BA1 (stand alone): Allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles) and 14.50% in gnomAD v4.1 (233,804/1,612,992 alleles) far exceeds the BA1 threshold of >1% for generic ACMG. Highest subpopulation frequency is 48.47% in East Asian (gnomAD v2.1). The variant is observed in 8,420 homozygous individuals in v2.1 and 26,307 in v4.1.
BS2 (strong): Observed in 8,420 homozygous individuals in gnomAD v2.1 and 26,307 in v4.1, with no reported severe disease phenotype. Homozygous observation in a gene where germline LoF is associated with an autosomal dominant/recessive cancer predisposition syndrome strongly supports a benign interpretation.
BP4 (supporting): SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant, but the absence of any predicted splicing alteration supports a benign interpretation.
BP6 (supporting): ClinVar reports this variant as Benign by 3 clinical laboratories (GeneDx, ARUP Laboratories, Labcorp Genetics). Although the review status is 1-star (criteria provided, single submitter), three independent clinical laboratories agree on a benign classification, which constitutes a reputable source under generic ACMG BP6.
BP7 (supporting): This is an intronic variant at position +14 from the exon 6 donor site with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. BP7 applies to synonymous and intronic variants where splicing prediction algorithms predict no impact on the splice consensus sequence.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 0 Benign evidence criteria: 5

Pathogenic criteria applied · 0

No pathogenic criterion marked as applied in the recorded assessment.

Benign criteria applied · 5

BA1Stand alone

BA1 · stand alone

Allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles) and 14.50% in gnomAD v4.1 (233,804/1,612,992 alleles) far exceeds the BA1 threshold of >1% for generic ACMG. Highest subpopulation frequency is 48.47% in East Asian (gnomAD v2.1). The variant is observed in 8,420 homozygous individuals in v2.1 and 26,307 in v4.1.

BS2Strong

BS2 · strong

Observed in 8,420 homozygous individuals in gnomAD v2.1 and 26,307 in v4.1, with no reported severe disease phenotype. Homozygous observation in a gene where germline LoF is associated with an autosomal dominant/recessive cancer predisposition syndrome strongly supports a benign interpretation.

BP4Supporting

BP4 · supporting

SpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant, but the absence of any predicted splicing alteration supports a benign interpretation.

BP6Supporting

BP6 · supporting

ClinVar reports this variant as Benign by 3 clinical laboratories (GeneDx, ARUP Laboratories, Labcorp Genetics). Although the review status is 1-star (criteria provided, single submitter), three independent clinical laboratories agree on a benign classification, which constitutes a reputable source under generic ACMG BP6.

BP7Supporting

BP7 · supporting

This is an intronic variant at position +14 from the exon 6 donor site with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. BP7 applies to synonymous and intronic variants where splicing prediction algorithms predict no impact on the splice consensus sequence.

Recorded classification: Benign

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BA1 stand-alone benign, BS2 strong benign, BP4 supporting benign, BP6 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 1 strong benign + 3 supporting benign, which maps to Benign.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1

gnomAD v2.1

Population frequency

233,804 / 1,612,992 alleles

gnomAD v4.1: 233,804 / 1,612,992 alleles. Recorded AF 0.144951. Recorded homozygote count 26307.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.195497; MAF= 19.54969%, 55283/282782 alleles, homozygotes = 8420) and has highest observed frequency in the East Asian population (AF= 0.484706; MAF= 48.47056%, 9666/19942 alleles, homozygotes = 2374); grpmax FAF= 0.476196.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.1828804347826087, 3365/18400 alleles, homozygotes = 464).

Applied · BA1, BS2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4, BP7 → SpliceAI ↗

ClinVar submissions

3 reported laboratory submissions

3 Benign. ClinVar API review status: criteria provided, multiple submitters, no conflicts.

Applied · BP6 → ClinVar ↗

No screenshot for this evidence

Functional evidence

Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗

Somatic evidence

No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Context only COSMIC ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 5 met · 14 not met · 0 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001276270.2:c.1543+14C>T is an intronic variant in MBD4 with an allele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles, 8,420 homozygotes), far exceeding the BA1 stand-alone benign threshold.

The variant is present in homozygous state in 8,420 individuals in gnomAD v2.1 and 26,307 in gnomAD v4.1, meeting BS2 at strong benign strength, inconsistent with a pathogenic role in MBD4-associated disease.

SpliceAI predicts no splicing impact (max delta score = 0.00) for this +14 intronic variant, consistent with BP4 and BP7 at supporting benign strength.

ClinVar reports this variant as Benign by 3 clinical laboratories (variation ID 1236364), meeting BP6 at supporting benign strength.

Met · 5

BA1 Stand aloneAllele frequency of 19.55% in gnomAD v2.1 (55,283/282,782 alleles) and 14.50% in gnomAD v4.1 (233,804/1,612,992 alleles) far exceeds the BA1 threshold of >1% for generic ACMG. Highest subpopulation frequency is 48.47% in East Asian (gnomAD v2.1). The variant is observed in 8,420 homozygous individuals in v2.1 and 26,307 in v4.1. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: total AF=19.55% (55
283/282
782 alleles
8
420 homozygotes)
grpmax FAF=0.476.
gnomAD v4.1: total AF=14.50% (233
804/1
612
992 alleles
26
307 homozygotes)
grpmax FAF=0.471.
East Asian subpopulation AF=48.47% (v2.1
9
666/19
942 alleles
2
374 homozygotes).
African/African American subpopulation AF=47.47% (v4.1
35
558/74
900 alleles
500 homozygotes).

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 StrongObserved in 8,420 homozygous individuals in gnomAD v2.1 and 26,307 in v4.1, with no reported severe disease phenotype. Homozygous observation in a gene where germline LoF is associated with an autosomal dominant/recessive cancer predisposition syndrome strongly supports a benign interpretation. Details ▾Hide ▴

Evidence considered

8
420 homozygotes in gnomAD v2.1.
26
307 homozygotes in gnomAD v4.1.
Homozygous state observed across multiple subpopulations
inconsistent with a pathogenic variant in a disease-associated gene.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant, but the absence of any predicted splicing alteration supports a benign interpretation. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta = 0.00
no predicted acceptor gain/loss or donor gain/loss.
REVEL and BayesDel not available for intronic variants.

Sources

spliceai ↗

BP6 SupportingClinVar reports this variant as Benign by 3 clinical laboratories (GeneDx, ARUP Laboratories, Labcorp Genetics). Although the review status is 1-star (criteria provided, single submitter), three independent clinical laboratories agree on a benign classification, which constitutes a reputable source under generic ACMG BP6. Details ▾Hide ▴

Evidence considered

ClinVar variation ID 1236364: Benign classification.
3 clinical laboratories: GeneDx
ARUP Laboratories
Labcorp Genetics (formerly Invitae).
Review status: criteria provided
single submitter (1-star
not 3-star expert panel).

Still missing

No 3-star expert panel review available for this variant.

Sources

clinvar ↗

BP7 SupportingThis is an intronic variant at position +14 from the exon 6 donor site with SpliceAI delta score of 0.00, indicating no predicted impact on splicing. BP7 applies to synonymous and intronic variants where splicing prediction algorithms predict no impact on the splice consensus sequence. Details ▾Hide ▴

Evidence considered

Intronic variant at c.1543+14 (14 bases downstream of exon 6).
SpliceAI max delta = 0.00
no predicted alteration of splicing.
No impact on canonical splice donor or acceptor sites.

Sources

spliceai ↗

Not met · 14 · evaluated, threshold not reached

PS2 No de novo observation reported for this variant in the available case materials. Details ▾Hide ▴

Evidence considered

No de novo report identified in ClinVar submissions or literature.

Still missing

No segregation or family study data available.

PS3 No functional data exists for this intronic variant. Neither the two ClinVar-cited publications (PMID:25741868, PMID:28492532) nor any other source provides variant-specific functional evidence. Details ▾Hide ▴

Evidence considered

No functional studies identified. Intronic +14 variant without published experimental characterization.

Still missing

No functional studies in the literature for this variant.

PS4 Variant is extremely common in population databases (gnomAD AF ~19.5%), precluding a statistically increased prevalence in affected individuals for any rare disease. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=19.55%
v4.1 AF=14.50%
8
420 and 26
307 homozygotes respectively.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM2 Variant is present at very high frequency in gnomAD (v2.1 AF=19.55%, v4.1 AF=14.50%), far exceeding the PM2 threshold of <0.1%. Does not meet the absence/low-frequency requirement. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 55
283/282
782 alleles (19.55%)
grpmax FAF=0.476. Approximately 8
420 homozygotes.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM6 No de novo observation reported for this variant. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴

Evidence considered

No de novo report identified in available data.

Still missing

No family studies available.

PP1 No co-segregation data available. Given the variant's extreme population frequency (~19.5%), co-segregation with any rare Mendelian disease would not be expected. Details ▾Hide ▴

Evidence considered

No segregation studies identified.

Still missing

No family segregation data available.

PP3 SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel scores are not available for this intronic variant. No in silico tool predicts a pathogenic effect. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00. REVEL/BayesDel/HCI prior: not available (intronic variant).

Sources

spliceai ↗

PP4 Variant is present in ~19.5% of the general population, which is incompatible with a variant causing a rare disease with high specificity. The phenotype specificity required for PP4 cannot be met. Details ▾Hide ▴

Evidence considered

Extremely high population frequency precludes phenotype-specific association.

Still missing

No phenotype data available for observed cases.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PP5 ClinVar reports this variant as Benign, not Pathogenic. PP5 requires a pathogenic assertion from a reputable source. ClinVar review status is 1-star (criteria provided, single submitter), not 3-star expert panel. Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign (variation ID 1236364
3 clinical laboratories). No pathogenic assertions exist.

Sources

clinvar ↗

BS3 No functional studies demonstrating no deleterious effect for this variant are available. SpliceAI delta of 0.00 indicates no splicing impact but is addressed under BP4/BP7 rather than BS3. Details ▾Hide ▴

Evidence considered

No in vitro or in vivo functional studies identified for this variant.

Still missing

No dedicated functional studies for this variant.

BS4 No segregation data available. However, given the extreme population frequency, lack of segregation with disease can be inferred but no formal study exists in the case materials. Details ▾Hide ▴

Evidence considered

No segregation studies available in case materials.

Still missing

No formal segregation analysis.

BP2 No observation of this variant in trans with a known pathogenic variant is reported in the case materials. Details ▾Hide ▴

Evidence considered

No co-occurrence data with pathogenic variants available.

Still missing

No phase data for observations in trans.

BP5 No alternate molecular basis for disease has been identified in cases with this variant in the available materials. Details ▾Hide ▴

Evidence considered

No alternate cause data available.

Still missing

No phenotype or alternate diagnosis data available.

PS5 Variant is classified as Benign (not Pathogenic) by all ClinVar submitters. PS5 requires a pathogenic assertion from a reputable source. Details ▾Hide ▴

Evidence considered

ClinVar classification: Benign (3 clinical laboratories
criteria provided single submitter).

Sources

clinvar ↗

Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AIntronic variant at position c.1543+14, outside canonical +/-1,2 splice consensus. Does not qualify as a null variant under the ClinGen SVI PVS1 decision framework (PMC6185798). Details ▾Hide ▴

Evidence considered

Intronic variant at +14 from exon 6 donor site
not a nonsense
frameshift
or canonical splice site variant.

Sources

pvs1_generic_framework ↗

PS1 N/AIntronic variant with no coding amino acid change. PS1 requires a different nucleotide change at the same position resulting in the same predicted protein consequence. Details ▾Hide ▴

No further detail was recorded.

PM1 N/AIntronic variant that does not map to a protein functional domain. PM1 requires the variant to be located in a well-established functional domain or critical hotspot. Details ▾Hide ▴

Evidence considered

Intronic position +14
no protein domain mapping applicable.

PM5 N/AIntronic variant with no protein residue context. PM5 requires a different pathogenic missense change at the same amino acid residue. Details ▾Hide ▴

Evidence considered

Variant is intronic
no amino acid residue position. PM5 candidates confirmed not_applicable.

PP2 N/ANot a missense variant. PP2 applies only to missense variants in genes with a low rate of benign missense variation. Details ▾Hide ▴

Evidence considered

Intronic variant
no amino acid change.

BS1 N/ABA1 is met at stand-alone benign strength. BS1 (>0.3% threshold) is superseded by the higher BA1 finding. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ANot a missense variant. BP1 applies specifically to missense variants in genes where truncating variants are the primary disease mechanism. Details ▾Hide ▴

Evidence considered

Intronic variant
no amino acid change.

Identifiers

Gene: MBD4
Transcript: NM_001276270.2
Coding (HGVS c.): NM_001276270.2:c.1543+14C>T
Protein (HGVS p.): NP_001263199.1:p.?
GRCh38: chr3:129433084 G>A
GRCh37: chr3:129151927 G>A
ClinVar: 1236364

Gene diagram

Every interpreted variant in MBD4, mapped onto the exon structure of NM_001276270.2. Select a row to find it on the plot.

MBD4NM_001276270.2

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

—

Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in MBD4 — Select a row to find it on the plot; use the link to open its page.

	Protein	Location	Classification	Link

gnomAD v4.1 233,804 / 1,612,992 alleles AF 0.145 · 26307 homozygotes · FAF 0.471

gnomAD v2.1 55,283 / 282,782 alleles AF 0.195 · 8420 homozygotes · FAF 0.476

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.14 · 233804 / 1,612,992 alleles · 26307 hom · FAF 0.47

African/African American35558 / 74,900	0.478500 hom
East Asian19716 / 44,858	0.444415 hom
South Asian24706 / 91,044	0.273588 hom
Admixed American14754 / 60,008	0.251886 hom
Middle Eastern1072 / 6,060	0.18115 hom
Ashkenazi Jewish5147 / 29,586	0.17463 hom
Remaining individuals10826 / 62,474	0.171223 hom
Amish96 / 908	0.115 hom
European (non-Finnish)119032 / 1,179,132	0.16031 hom
European (Finnish)2897 / 64,022	0.04581 hom

gnomAD v2.1

AF 0.2 · 55283 / 282,782 alleles · 8420 hom · FAF 0.48

East Asian9666 / 19,942	0.482374 hom
African/African American11883 / 24,948	0.482831 hom
South Asian8338 / 30,612	0.271216 hom
Admixed American8425 / 35,428	0.241069 hom
Ashkenazi Jewish1787 / 10,370	0.17153 hom
Remaining individuals1174 / 7,224	0.16109 hom
European (non-Finnish)12916 / 129,144	0.1641 hom
European (Finnish)1094 / 25,114	0.04427 hom

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.144951; MAF= 14.49505%, 233804/1612992 alleles, homozygotes = 26307) and has highest observed frequency in the African/African American population (AF= 0.47474; MAF= 47.47397%, 35558/74900 alleles, homozygotes = 8500); grpmax FAF= 0.470605.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.1828804347826087, 3365/18400 alleles, homozygotes = 464).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

SpliceAI acceptor lossat +180 bp

0.000

SpliceAI acceptor gainat +163 bp

0.000

SpliceAI donor lossat +108 bp

0.000

SpliceAI donor gainat +14 bp

0.000

Pangolin splice lossmagnitude shown

-0.000

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI: max delta = 0.00
no predicted acceptor gain/loss or donor gain/loss.
REVEL and BayesDel not available for intronic variants.

Sources

spliceai ↗

Evidence considered

Intronic variant at c.1543+14 (14 bases downstream of exon 6).
SpliceAI max delta = 0.00
no predicted alteration of splicing.
No impact on canonical splice donor or acceptor sites.

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00. REVEL/BayesDel/HCI prior: not available (intronic variant).

Sources

spliceai ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.

Richards S et al. · 2015

Standards and guidelines for the interpretation of sequence variants (ACMG/AMP 2015). This is a methodological framework paper and does not mention NM_001276270.2:c.1543+14C>T or any MBD4 variant.
Does not name this variant
PMID 25741868 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.

Nykamp K et al. · 2017

Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. This is a framework refinement paper and does not mention NM_001276270.2:c.1543+14C>T or any MBD4 variant.
Does not name this variant
PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 233,804 / 1,612,992 recorded alleles Open source ↗

gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗

SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗

ClinVar 3 Benign Open source ↗

COSMIC Captured COSMIC source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.1828804347826087, 3365/18400 alleles, homozygotes = 464).

ClinVar

This variant has been reported in ClinVar as Benign (3 clinical laboratories). (ClinVarID = 1236364)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

Somatic

This variant has not previously been reported in somatic cancers (COSMIC).