Variant classification summary

NM_022552.4:c.1475-19C>T

DNMT3A · NP_072046.2:p.? · NM_022552.4

GRCh37: chr2:25468220 G>A · GRCh38: chr2:25245351 G>A

Gene: DNMT3A Transcript: NM_022552.4

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

DNMT3A

Transcript

NM_022552.4

Protein

NP_072046.2:p.?

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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

2

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%.

3

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.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	Not met	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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 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.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional or RNA study showing a damaging effect for this variant was identified.
PS4	Not assessed	No case-control enrichment data or multiple independent affected-case observations were identified for this variant.	clinvar
PM1	Not assessed	No evidence was identified that this intronic position lies in a mutational hot spot or other well-established critical functional region without benign variation.
PM2	Met	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 gnomad_v4
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.
PM5	N/A	PM5 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.
PM6	Not assessed	No assumed or incompletely confirmed de novo observation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is a missense-specific criterion and is not applicable to this intronic variant.
PP3	Not met	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.	spliceai
PP4	Not assessed	No phenotype information was identified that would allow assessment of a highly specific DNMT3A-related clinical presentation for this variant.
PP5	N/A	A pathogenic assertion from another source without accessible primary evidence was not used for this criterion. PP5 was not applied.
BA1	Not met	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%.	gnomad_v4
BS1	Not met	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%.	gnomad_v4
BS2	Not assessed	The available population data do not establish observation in clearly unaffected individuals at a level sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional or RNA study showing normal splicing or normal function for this variant was identified.
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	N/A	BP1 is a missense-specific criterion and is not applicable to this intronic variant.
BP2	Not assessed	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.
BP3	N/A	BP3 applies to in-frame variants in repetitive regions without known function and is not applicable to this intronic single-nucleotide variant.
BP4	Not assessed	Benign computational evidence for this intronic variant is captured under BP7 rather than counted separately here.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular cause that would explain a reported phenotype independently of this variant.
BP6	N/A	A benign assertion from another source without accessible primary evidence was not used as stand-alone evidence for this criterion. BP6 was not applied.
BP7	Met	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.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.