MBD4c.335+27T>CBenign

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Variant interpretation report

MBD4 c.335+27T>C, p.?

NM_001276270.2:c.335+27T>C 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) · 2 strong (benign) · 2 supporting (benign)
Expert rules: Not recorded
Other laboratories (ClinVar): 1 Benign
Pipeline record: 4 Aug 2026 · version 7.0.6

Evidence considered

View criteria

Applied evidence criteria

BA1 (stand alone): This variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles, 2,605 homozygotes) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles, 11,308 homozygotes). The grpmax filtering allele frequency is 24.3%. These frequencies far exceed the 1% BA1 threshold, establishing this variant as a common benign polymorphism.
BS1 (strong): This variant is present at 11.6% in gnomAD v2.1, far exceeding the 0.3% BS1 threshold. Allele frequency is more than 38-fold above the cutoff across multiple populations, including South Asian (24.8%), African/African American (21.8%), and Ashkenazi Jewish (16.7%).
BS2 (strong): This variant has been observed in 2,605 homozygotes in gnomAD v2.1 and 11,308 homozygotes in gnomAD v4.1. Homozygosity for this variant is tolerated at population scale, inconsistent with a fully penetrant Mendelian disorder.
BP4 (supporting): SpliceAI predicts no splicing impact (max delta score = 0.00) for this intronic variant. No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. Computational evidence supports a benign interpretation.
BP7 (supporting): This is an intronic variant (c.335+27T>C) at a position not within the canonical splice consensus. SpliceAI predicts no splicing impact (max delta = 0.00). No evidence suggests this variant disrupts splicing, consistent with BP7.

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

This variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles, 2,605 homozygotes) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles, 11,308 homozygotes). The grpmax filtering allele frequency is 24.3%. These frequencies far exceed the 1% BA1 threshold, establishing this variant as a common benign polymorphism.

BS1Strong

BS1 · strong

This variant is present at 11.6% in gnomAD v2.1, far exceeding the 0.3% BS1 threshold. Allele frequency is more than 38-fold above the cutoff across multiple populations, including South Asian (24.8%), African/African American (21.8%), and Ashkenazi Jewish (16.7%).

BS2Strong

BS2 · strong

This variant has been observed in 2,605 homozygotes in gnomAD v2.1 and 11,308 homozygotes in gnomAD v4.1. Homozygosity for this variant is tolerated at population scale, inconsistent with a fully penetrant Mendelian disorder.

BP4Supporting

BP4 · supporting

SpliceAI predicts no splicing impact (max delta score = 0.00) for this intronic variant. No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. Computational evidence supports a benign interpretation.

BP7Supporting

BP7 · supporting

This is an intronic variant (c.335+27T>C) at a position not within the canonical splice consensus. SpliceAI predicts no splicing impact (max delta = 0.00). No evidence suggests this variant disrupts splicing, consistent with BP7.

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, BS1 strong benign, BS2 strong benign, BP4 supporting benign, BP7 supporting benign; combination = 1 stand-alone benign + 2 strong benign + 2 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

165,627 / 1,501,376 alleles

gnomAD v4.1: 165,627 / 1,501,376 alleles. Recorded AF 0.110317. Recorded homozygote count 11308.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0.116205; MAF= 11.62048%, 32839/282596 alleles, homozygotes = 2605) and has highest observed frequency in the South Asian population (AF= 0.248186; MAF= 24.81862%, 7594/30598 alleles, homozygotes = 1010); grpmax FAF= 0.24352.

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.12480990658266349, 2298/18412 alleles, homozygotes = 167).

Applied · BA1, BS1, 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

1 reported laboratory submissions

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

Context only 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

1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV51445979, n = 1 times).

Context only COSMIC ↗

For specialists

Technical detail

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

29 criteria with recorded statuses: 5 met · 14 not met · 0 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

NM_001276270.2:c.335+27T>C is a common intronic variant with an allele frequency of 11.6% in gnomAD v2.1 (32,839/282,596 alleles, 2,605 homozygotes) and 11.0% in gnomAD v4.1 (165,627/1,501,376 alleles, 11,308 homozygotes), far exceeding the 1% threshold for stand-alone benign (BA1).

The variant has been reported as Benign in ClinVar (ClinVar ID 1249121) by a clinical laboratory using criteria-based assessment.

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a deep intronic variant that does not disrupt normal mRNA processing (BP4, BP7).

The variant has been observed in homozygous state in 2,605 individuals in gnomAD v2.1 and 11,308 in gnomAD v4.1, demonstrating that homozygosity is tolerated at population scale (BS2).

Based on BA1 alone, this variant meets stand-alone benign criteria and is classified as Benign per the ACMG/AMP 2015 combining rules regardless of any other criterion.

Met · 5

BA1 Stand aloneThis variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles, 2,605 homozygotes) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles, 11,308 homozygotes). The grpmax filtering allele frequency is 24.3%. These frequencies far exceed the 1% BA1 threshold, establishing this variant as a common benign polymorphism. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: AF=11.62%
2
605 homozygotes
grpmax FAF=24.35%. gnomAD v4.1: AF=11.03%
11
308 homozygotes
grpmax FAF=24.31%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS1 StrongThis variant is present at 11.6% in gnomAD v2.1, far exceeding the 0.3% BS1 threshold. Allele frequency is more than 38-fold above the cutoff across multiple populations, including South Asian (24.8%), African/African American (21.8%), and Ashkenazi Jewish (16.7%). Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=11.6%
exceeding 0.3% BS1 threshold. Elevated across all populations.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 StrongThis variant has been observed in 2,605 homozygotes in gnomAD v2.1 and 11,308 homozygotes in gnomAD v4.1. Homozygosity for this variant is tolerated at population scale, inconsistent with a fully penetrant Mendelian disorder. Details ▾Hide ▴

Evidence considered

2
605 homozygotes in gnomAD v2.1
11
308 homozygotes in gnomAD v4.1.

Sources

gnomad_v2 ↗gnomad_v4 ↗

BP4 SupportingSpliceAI predicts no splicing impact (max delta score = 0.00) for this intronic variant. No donor gain, donor loss, acceptor gain, or acceptor loss is predicted. Computational evidence supports a benign interpretation. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00: no donor gain
donor loss
acceptor gain
or acceptor loss predicted.

Sources

spliceai ↗

BP7 SupportingThis is an intronic variant (c.335+27T>C) at a position not within the canonical splice consensus. SpliceAI predicts no splicing impact (max delta = 0.00). No evidence suggests this variant disrupts splicing, consistent with BP7. Details ▾Hide ▴

Evidence considered

c.335+27T>C is an intronic variant outside the canonical splice consensus. SpliceAI max delta = 0.00 confirms no predicted splice disruption.

Sources

spliceai ↗

Not met · 14 · evaluated, threshold not reached

PS2 No de novo observation data available for this variant. Details ▾Hide ▴

Still missing

No de novo testing or family trio data available.

PS3 No variant-specific functional data available. This is a common intronic polymorphism (AF 11.6%) with SpliceAI delta score of 0.00, providing no indication of functional consequence. Details ▾Hide ▴

Still missing

No functional studies exist for this intronic variant.

PS4 This variant is present at 11.6% allele frequency in gnomAD v2.1 with 2,605 homozygotes; case enrichment cannot be established for a variant of this frequency in the general population. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=11.6% (32
839/282
596 alleles)
gnomAD v4.1 AF=11.0% (165
627/1
501
376 alleles).

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM2 This variant is present in gnomAD v2.1 at 11.6% (32,839/282,596 alleles) and gnomAD v4.1 at 11.0% (165,627/1,501,376 alleles), far exceeding the <0.1% threshold for PM2. It is a common polymorphism, not absent from population databases. Details ▾Hide ▴

Evidence considered

gnomAD v2.1 AF=11.6%
gnomAD v4.1 AF=11.0%.

Sources

gnomad_v2 ↗gnomad_v4 ↗

PM6 No de novo observation data available for this variant. Details ▾Hide ▴

Still missing

No de novo data in ClinVar or literature.

PP1 No cosegregation data available for this variant. Details ▾Hide ▴

Still missing

No family segregation studies available.

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

Evidence considered

SpliceAI max delta = 0.00
predicting no donor/acceptor gain or loss.

Sources

spliceai ↗

PP4 No patient phenotype data available to evaluate whether the variant explains a specific clinical presentation. Details ▾Hide ▴

Still missing

No phenotype or clinical data provided for this case.

PP5 ClinVar reports this variant as Benign, not Pathogenic. PP5 requires a pathogenic classification from a reputable source with supporting evidence. Furthermore, ClinVar review status is 'criteria provided, single submitter' (not 3-star expert panel), which does not meet the threshold for PP5 application. Details ▾Hide ▴

Evidence considered

ClinVar ID 1249121: Benign
single submitter
not expert panel.

Sources

clinvar ↗

BS3 No functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴

Still missing

No functional studies available.

BS4 No family segregation data available to assess non-segregation with disease. Details ▾Hide ▴

Still missing

No family studies available.

BP2 No specific data on observation in trans with a pathogenic variant were identified in the case materials. Although the high population frequency (11.6%) makes co-occurrence statistically inevitable, direct evidence was not located. Details ▾Hide ▴

Still missing

No documented observation in trans with a known pathogenic MBD4 variant.

BP5 No data available indicating an alternate molecular basis for disease in individuals carrying this variant. Details ▾Hide ▴

Still missing

No alternate molecular diagnosis data provided.

BP6 ClinVar reports this variant as Benign (ClinVar ID 1249121), but the review status is 'criteria provided, single submitter' — not a 3-star expert panel classification. Per adjudication rules, BP6 is applied only with ClinVar 3-star expert panel support, which is not met here. Details ▾Hide ▴

Evidence considered

ClinVar ID 1249121: Benign
single submitter. Not 3-star expert panel.

Sources

clinvar ↗

Not applicable · 10· recorded as not applicable Show reasons ▾Hide reasons ▴

PVS1 N/AThis intronic variant (c.335+27T>C) is not a canonical null variant (nonsense, frameshift, or ±1,2 splice consensus); PVS1 is not applicable per ClinGen SVI PVS1 guidelines (PMC6185798). Details ▾Hide ▴

Evidence considered

Variant classified as 'other' bucket in PVS1 variant assessment
apply_generic_pvs1_framework is false.

Sources

pvs1_variant_assessment

PS1 N/AThis is an intronic variant with no amino acid change; PS1 (same amino acid change via different nucleotide substitution) does not apply. Details ▾Hide ▴

No further detail was recorded.

PM1 N/AThis is an intronic variant (c.335+27T>C) located outside coding sequence; PM1 (location in a critical functional domain) applies only to protein-coding regions or residues. Details ▾Hide ▴

No further detail was recorded.

PM3 N/ASkipped: trivially not applicable (recessive trans criterion, not a recessive disorder context). Details ▾Hide ▴

No further detail was recorded.

PM4 N/ASkipped: trivially not applicable (protein length change criterion; this is an intronic substitution). Details ▾Hide ▴

No further detail was recorded.

PM5 N/AThis is an intronic variant with no amino acid change; PM5 (novel missense at a residue where a different pathogenic missense exists) does not apply. Details ▾Hide ▴

Evidence considered

PM5 candidate harvesting confirmed not applicable: unable to parse missense residue context
variant is intronic.

Sources

pm5_candidates

PP2 N/AThis is an intronic variant, not a missense change; PP2 (missense variant in a gene with low rate of benign missense variation) does not apply. Details ▾Hide ▴

No further detail was recorded.

BP1 N/AThis is an intronic variant; BP1 (missense variant in a gene where truncating variants are the primary disease mechanism) does not apply. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ASkipped: trivially not applicable (in-frame indel criterion). Details ▾Hide ▴

No further detail was recorded.

PS5 N/AThis is an intronic variant with no amino acid change; PS5 (different nucleotide change at same position producing same amino acid change as a known pathogenic variant) does not apply. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: MBD4
Transcript: NM_001276270.2
Coding (HGVS c.): NM_001276270.2:c.335+27T>C
Protein (HGVS p.): NP_001263199.1:p.?
GRCh38: chr3:129437693 A>G
GRCh37: chr3:129156536 A>G
ClinVar: 1249121
COSMIC: COSV51445979

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

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Transcript span

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Strand

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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 v4.1 165,627 / 1,501,376 alleles AF 0.11 · 11308 homozygotes · FAF 0.243

gnomAD v2.1 32,839 / 282,596 alleles AF 0.116 · 2605 homozygotes · FAF 0.244

gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 0.11 · 165627 / 1,501,376 alleles · 11308 hom · FAF 0.24

South Asian21835 / 88,808	0.252938 hom
African/African American16003 / 72,632	0.221816 hom
Ashkenazi Jewish4838 / 28,924	0.17415 hom
Middle Eastern915 / 5,844	0.1690 hom
Remaining individuals7146 / 58,664	0.12495 hom
Amish96 / 912	0.115 hom
European (non-Finnish)104321 / 1,077,340	0.0975112 hom
Admixed American4898 / 59,880	0.082243 hom
East Asian2933 / 44,390	0.066126 hom
European (Finnish)2642 / 63,982	0.04168 hom

gnomAD v2.1

AF 0.12 · 32839 / 282,596 alleles · 2605 hom · FAF 0.24

South Asian7594 / 30,598	0.251010 hom
African/African American5428 / 24,934	0.22607 hom
Ashkenazi Jewish1728 / 10,366	0.17139 hom
Remaining individuals846 / 7,210	0.1259 hom
European (non-Finnish)12241 / 129,032	0.095590 hom
East Asian1528 / 19,952	0.07766 hom
Admixed American2484 / 35,398	0.07111 hom
European (Finnish)990 / 25,106	0.03923 hom

gnomAD-Canada

AF not recorded · ? / ? alleles

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 0.110317; MAF= 11.03168%, 165627/1501376 alleles, homozygotes = 11308) and has highest observed frequency in the South Asian population (AF= 0.245867; MAF= 24.58675%, 21835/88808 alleles, homozygotes = 2938); grpmax FAF= 0.243137.

gnomAD v2.1

gnomAD-Canada

This variant is present in gnomAD-Canada v1.0 (AF= 0.12480990658266349, 2298/18412 alleles, homozygotes = 167).

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown

-0.020

Pangolin splice gain

0.010

Other predictors

REVEL: Not available
BayesDel: Not available

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00: no donor gain
donor loss
acceptor gain
or acceptor loss predicted.

Sources

spliceai ↗

Evidence considered

c.335+27T>C is an intronic variant outside the canonical splice consensus. SpliceAI max delta = 0.00 confirms no predicted splice disruption.

Sources

spliceai ↗

Evidence considered

SpliceAI max delta = 0.00
predicting no donor/acceptor gain or loss.

Sources

spliceai ↗

Statement

In silico

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

1 paper record 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

The 2015 ACMG/AMP standards and guidelines for the interpretation of sequence variants (Richards et al.). This is a general methodological framework paper that does not discuss MBD4 or any specific variant.
Does not name this variant
PMID 25741868 ↗

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

gnomAD v4.1 165,627 / 1,501,376 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 1 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= 0.12480990658266349, 2298/18412 alleles, homozygotes = 167).

ClinVar

This variant has been reported in ClinVar as Benign (1 clinical laboratory). (ClinVarID = 1249121)

In silico

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

Somatic

This variant has previously been reported in somatic cancers (COSMIC; COSV51445979, n = 1 times).