Classification rationale

PM2 BP7 VUS

DNMT3A c.1475-19C>T

The DNMT3A c.1475-19C>T (p.?) variant has been reported in ClinVar with a Likely benign classification from a single clinical laboratory.¹ 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%.² 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.³

PM2 + BP7 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗

3 spliceai ↗

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.

Gene diagram · NM_022552.4 · variants mapped to exon structure

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 17 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 2

Strength Supporting Moderate Strong Very strong

PM2 supporting review Pathogenic

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%.

gnomAD v2.1 total AF 8.06816e-06gnomAD v4.1 total AF 4.34395e-06gnomAD v4.1 Middle Eastern AF 0.000493583

gnomad_v2 ↗gnomad_v4 ↗

BP7 supporting review Benign

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.

intronic position c.1475-19SpliceAI max delta 0.00

spliceai ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

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.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional or RNA study showing a damaging effect for this variant was identified.

PS4 No case-control enrichment data or multiple independent affected-case observations were identified for this variant.

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.

PM6 No assumed or incompletely confirmed de novo observation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP3 Available computational evidence does not support a damaging splicing effect.

PP4 No phenotype information was identified that would allow assessment of a highly specific DNMT3A-related clinical presentation for this variant.

Benign

BA1 Population frequency does not reach the benign stand-alone threshold.

BS1 Population frequency does not exceed the benign strong threshold.

BS2 The available population data do not establish observation in clearly unaffected individuals at a level sufficient for BS2.

BS3 No well-established functional or RNA study showing normal splicing or normal function for this variant was identified.

BS4 No non-segregation data were identified for this variant.

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.

BP4 Benign computational evidence for this intronic variant is captured under BP7 rather than counted separately here.

BP5 No evidence was identified for an alternate molecular cause that would explain a reported phenotype independently of this variant.

N/A · 9 PS1 · PM3 · PM4 · PM5 · PP2 · PP5 · BP1 · BP3 · BP6

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

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.

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).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00043% · 7 / 1,611,438
0 hom · FAF 0.013%

Middle Eastern 3 / 6,078	0.049%
Remaining individuals 1 / 62,394	0.0016%
South Asian 1 / 90,748	0.0011%
European (non-Finnish) 2 / 1,178,232	0.00017%

+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.00081% · 2 / 247,888
0 hom

South Asian 1 / 30,254	0.0033%
European (non-Finnish) 1 / 111,706	0.0009%

+ 6 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)

gnomAD v4 ↗ gnomAD v2 ↗

ClinVar

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

ClinVar ↗

In silico

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

SpliceAI ↗

Functional No data

No calibrated functional assay or RNA evidence was identified for this variant.

OncoKB ↗

COSMIC

Somatic evidence

COSMIC

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

Hotspots

This variant does not lie in a statistically significant cancer hotspot.

COSMIC ↗

Sources & reference links

6Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

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