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DNMT3Ac.1475-19C>TUncertain significance
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Variant interpretation report

DNMT3A c.1475-19C>T, p.?

NM_022552.4:c.1475-19C>T NP_072046.2:p.? View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

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

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About DNMT3A

No gene-level summary was recorded for this case.

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: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

This variant is present at very low frequency in population databases, with gnomAD v2.1 AF 0.00081% (2/247888 alleles) and gnomAD v4.1 AF 0.00043% (7/1611438 alleles). The highest observed population frequency is 0.04936% in gnomAD v4.1 Middle Eastern samples, which remains below the default PM2 threshold of 0.1%.

Benign criteria applied · 1
BP7Supporting
BP7 · supporting

This intronic variant is outside the canonical splice consensus at c.1475-19, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This supports BP7 for a noncoding intronic change without computational evidence for abnormal splicing.

Recorded classification: Uncertain significance

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP7 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.

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
7 / 1,611,438 alleles

gnomAD v4.1: 7 / 1,611,438 alleles. Recorded AF 4.34395e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.06816e-06; MAF= 0.00081%, 2/247888 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.30535e-05; MAF= 0.00331%, 1/30254 alleles, homozygotes = 0).

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗
No screenshot for this evidence
Computational predictions
Not recorded

No SpliceAI or REVEL score is recorded in the fields used for this tile.

Applied · BP7 →
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

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
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only COSMIC ↗
For specialists

Technical detail

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

28 criteria with recorded statuses: 2 met · 4 not met · 13 not assessed · 9 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

The DNMT3A c.1475-19C>T (p.?) variant has been reported in ClinVar with a Likely benign classification from a single clinical laboratory.

This variant is present at very low overall frequency in population databases, with gnomAD v2.1 AF 0.00081% (2/247888 alleles) and gnomAD v4.1 AF 0.00043% (7/1611438 alleles); the highest observed frequency is 0.04936% in the Middle Eastern population in gnomAD v4.1, which is below the default BS1 threshold of 0.3% and below the BA1 threshold of 1.0%.

SpliceAI predicts no significant splice impact for this variant, with a maximum delta score of 0.00, which supports a benign computational interpretation rather than evidence for abnormal splicing.

Met · 2

PM2 SupportingThis variant is present at very low frequency in population databases, with gnomAD v2.1 AF 0.00081% (2/247888 alleles) and gnomAD v4.1 AF 0.00043% (7/1611438 alleles). The highest observed population frequency is 0.04936% in gnomAD v4.1 Middle Eastern samples, which remains below the default PM2 threshold of 0.1%. Details ▾Hide ▴
Rule
Default non-VCEP population threshold: PM2 if AF < 0.1%.
Evidence considered
  • gnomAD v2.1 total AF 8.06816e-06
  • gnomAD v4.1 total AF 4.34395e-06
  • gnomAD v4.1 Middle Eastern AF 0.000493583
Still missing
  • Population frequency should be interpreted in the context of disease prevalence and penetrance during final review.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP7 SupportingThis intronic variant is outside the canonical splice consensus at c.1475-19, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This supports BP7 for a noncoding intronic change without computational evidence for abnormal splicing. Details ▾Hide ▴
Rule
BP7 can support a benign interpretation for intronic variants outside canonical splice positions when splicing prediction does not suggest impact.
Evidence considered
  • intronic position c.1475-19
  • SpliceAI max delta 0.00
Still missing
  • No direct RNA study was identified.
Sources
spliceai ↗

Not met · 4 · evaluated, threshold not reached

PVS1 Although germline loss of function is an established DNMT3A disease mechanism, this intronic variant is c.1475-19C>T, outside the canonical +/-1,2 splice consensus, and the generic PVS1 assessment does not place it in a default null-variant bucket. Available evidence does not support applying PVS1 at this stage. Details ▾Hide ▴
Rule
Generic PVS1 fallback only applies after gene-level loss-of-function eligibility is established and the variant fits a qualifying null/splice category.
Evidence considered
  • DNMT3A loss-of-function mechanism supported at the gene level
  • generic PVS1 scaffold did not recommend application for this -19 intronic variant
Still missing
  • No RNA study or other direct transcript evidence was identified for this variant.
Sources
pvs1_gene_contextpvs1_variant_assessmentpvs1_generic_framework ↗
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI shows a maximum delta score of 0.00, and no REVEL or BayesDel score was available or relevant for this intronic noncoding change. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect.
Evidence considered
  • SpliceAI DS_AG 0.0
  • DS_AL 0.0
  • DS_DG 0.0
  • DS_DL 0.0
  • max delta 0.00
Still missing
  • No additional validated splicing prediction or RNA assay was identified.
Sources
spliceai ↗
BA1 Population frequency does not reach the benign stand-alone threshold. The highest observed frequency is 0.04936% in gnomAD v4.1 Middle Eastern samples, which is below the default BA1 threshold of 1.0%. Details ▾Hide ▴
Rule
Default non-VCEP population threshold: BA1 if AF > 1%.
Evidence considered
  • gnomAD v4.1 Middle Eastern AF 0.000493583
Sources
gnomad_v4 ↗
BS1 Population frequency does not exceed the benign strong threshold. The highest observed frequency is 0.04936% in gnomAD v4.1 Middle Eastern samples, which is below the default BS1 threshold of 0.3%. Details ▾Hide ▴
Rule
Default non-VCEP population threshold: BS1 if AF > 0.3%.
Evidence considered
  • gnomAD v4.1 Middle Eastern AF 0.000493583
Sources
gnomad_v4 ↗

Not assessed · 13 · no assessment recorded

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
  • No parental testing data were identified.
PS3 No well-established functional or RNA study showing a damaging effect for this variant was identified. Details ▾Hide ▴
Still missing
  • No patient RNA
  • minigene
  • or other direct functional assay was identified.
PS4 No case-control enrichment data or multiple independent affected-case observations were identified for this variant. Details ▾Hide ▴
Evidence considered
  • single ClinVar submitter only
Still missing
  • No affected-case series or prevalence comparison was identified.
Sources
clinvar ↗
PM1 No evidence was identified that this intronic position lies in a mutational hot spot or other well-established critical functional region without benign variation. Details ▾Hide ▴
Still missing
  • No domain or hotspot evidence specific to this intronic site was identified.
PM6 No assumed or incompletely confirmed de novo observation was identified for this variant. Details ▾Hide ▴
Still missing
  • No proband-only report with limited parental data was identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • No family studies showing co-segregation with disease were identified.
PP4 No phenotype information was identified that would allow assessment of a highly specific DNMT3A-related clinical presentation for this variant. Details ▾Hide ▴
Still missing
  • No individual-level phenotype data were identified.
BS2 The available population data do not establish observation in clearly unaffected individuals at a level sufficient for BS2. Details ▾Hide ▴
Evidence considered
  • no homozygotes reported
Still missing
  • No healthy adult carrier evidence specific to this criterion was identified.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No well-established functional or RNA study showing normal splicing or normal function for this variant was identified. Details ▾Hide ▴
Still missing
  • No benign functional assay or transcript study was identified.
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
  • No informative family study showing lack of segregation was identified.
BP2 No data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant in a way that supports BP2. Details ▾Hide ▴
Still missing
  • No phase data were identified.
BP4 Benign computational evidence for this intronic variant is captured under BP7 rather than counted separately here. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00
Sources
spliceai ↗
BP5 No evidence was identified for an alternate molecular cause that would explain a reported phenotype independently of this variant. Details ▾Hide ▴
Still missing
  • No individual-level phenotype and alternate-cause data were identified.
Not applicable · 9· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies to variants that produce the same amino acid change as a known pathogenic variant. This intronic variant has no established amino acid substitution, so PS1 is not applicable. Details ▾Hide ▴
Evidence considered
  • intronic variant with predicted protein consequence p.?
PM3 N/APM3 applies to recessive disorders with a variant observed in trans with a pathogenic variant. That evidence was not identified, and this criterion is not applicable here. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to protein length changes such as in-frame insertions or deletions and stop-loss variants. This intronic variant does not meet that criterion type. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to a novel missense change at an amino acid residue where a different pathogenic missense change is established. This intronic variant is not a missense variant, so PM5 is not applicable. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 is a missense-specific criterion and is not applicable to this intronic variant. Details ▾Hide ▴

No further detail was recorded.

PP5 N/AA pathogenic assertion from another source without accessible primary evidence was not used for this criterion. PP5 was not applied. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 is a missense-specific criterion and is not applicable to this intronic variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame variants in repetitive regions without known function and is not applicable to this intronic single-nucleotide variant. Details ▾Hide ▴

No further detail was recorded.

BP6 N/AA benign assertion from another source without accessible primary evidence was not used as stand-alone evidence for this criterion. BP6 was not applied. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
DNMT3A
Transcript
NM_022552.4
Coding (HGVS c.)
NM_022552.4:c.1475-19C>T
Protein (HGVS p.)
NP_072046.2:p.?
GRCh38
chr2:25245351 G>A
GRCh37
chr2:25468220 G>A

Gene diagram

Every interpreted variant in DNMT3A, mapped onto the exon structure of NM_022552.4. Select a row to find it on the plot.

DNMT3ANM_022552.4
Fetching transcript structure from UCSC…
gnomAD v4.1 7 / 1,611,438 alleles AF 4.34e-06 · 0 homozygotes · FAF 0.000134
gnomAD v2.1 2 / 247,888 alleles AF 8.07e-06 · 0 homozygotes

By genetic ancestry

gnomAD v4.1

AF 4.3e-06 · 7 / 1,611,438 alleles · 0 hom · FAF 0.00013
Middle Eastern3 / 6,078 0.00049
Remaining individuals1 / 62,394 1.6e-05
South Asian1 / 90,748 1.1e-05
European (non-Finnish)2 / 1,178,232 1.7e-06
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 8.1e-06 · 2 / 247,888 alleles · 0 hom
South Asian1 / 30,254 3.3e-05
European (non-Finnish)1 / 111,706 9e-06
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 4.34395e-06; MAF= 0.00043%, 7/1611438 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000493583; MAF= 0.04936%, 3/6078 alleles, homozygotes = 0); grpmax FAF= 0.00013368.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.06816e-06; MAF= 0.00081%, 2/247888 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.30535e-05; MAF= 0.00331%, 1/30254 alleles, homozygotes = 0).

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

BP7 SupportingThis intronic variant is outside the canonical splice consensus at c.1475-19, and SpliceAI predicts no significant splice effect with a maximum delta score of 0.00. This supports BP7 for a noncoding intronic change without computational evidence for abnormal splicing. Details ▾Hide ▴
Rule
BP7 can support a benign interpretation for intronic variants outside canonical splice positions when splicing prediction does not suggest impact.
Evidence considered
  • intronic position c.1475-19
  • SpliceAI max delta 0.00
Still missing
  • No direct RNA study was identified.
Sources
spliceai ↗
PP3 Available computational evidence does not support a damaging splicing effect. SpliceAI shows a maximum delta score of 0.00, and no REVEL or BayesDel score was available or relevant for this intronic noncoding change. Details ▾Hide ▴
Rule
PP3 requires computational evidence supporting a deleterious effect.
Evidence considered
  • SpliceAI DS_AG 0.0
  • DS_AL 0.0
  • DS_DG 0.0
  • DS_DL 0.0
  • max delta 0.00
Still missing
  • No additional validated splicing prediction or RNA assay was identified.
Sources
spliceai ↗
BP4 Benign computational evidence for this intronic variant is captured under BP7 rather than counted separately here. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta 0.00
Sources
spliceai ↗

Statement

In silico

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

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

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

gnomAD v4.1 7 / 1,611,438 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Captured SpliceAI source record Open source ↗
ClinVar Captured ClinVar source record 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

This variant is present in gnomAD v4.1 (AF= 4.34395e-06; MAF= 0.00043%, 7/1611438 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000493583; MAF= 0.04936%, 3/6078 alleles, homozygotes = 0); grpmax FAF= 0.00013368.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 8.06816e-06; MAF= 0.00081%, 2/247888 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.30535e-05; MAF= 0.00331%, 1/30254 alleles, homozygotes = 0).

ClinVar

This variant has been reported in ClinVar as Likely benign (1 clinical laboratory).

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).