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 ↗

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

DNMT3A NM_022552.4

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

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