Variant classification summary

NM_024426.4:c.1107A>G

WT1 · NP_077744.3:p.(Arg369=) · NM_024426.4

GRCh37: chr11:32417945 T>C · GRCh38: chr11:32396399 T>C

Gene: WT1 Transcript: NM_024426.4

Final call

Benign

BA1_stand-alone_benign BS1_strong_benign BP4_supporting_benign BP7_supporting_benign

Variant details

Gene

WT1

Transcript

NM_024426.4

Protein

NP_077744.3:p.(Arg369=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The WT1 c.1107A>G (p.Arg369=) variant has been reported in ClinVar as benign.

2

This variant is common in population databases, with an allele frequency of 0.235708 in gnomAD v2.1 and 0.180386 in gnomAD v4.1, which is far above benign population thresholds.

3

In silico evidence supports a benign interpretation because this synonymous change does not alter the encoded amino acid and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Benign classification because either BA1 is met or at least two strong benign criteria are present.

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	This variant is a synonymous change, WT1 c.1107A>G (p.Arg369=), and does not fall within the generic PVS1 null-variant categories for nonsense, frameshift, or canonical +/-1 or 2 splice-site variants.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	This criterion applies to a different nucleotide change that produces the same amino acid substitution as a known pathogenic variant. This variant is synonymous and no amino acid substitution is produced.
PS2	Not assessed	No confirmed de novo data with established maternity and paternity were identified for this variant.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified.
PS4	Not met	Available evidence does not show that this variant is enriched in individuals with WT1-related germline disease compared with controls. A ClinVar benign classification and very high population frequency argue against pathogenic case enrichment.	clinvar gnomad_v2 gnomad_v4
PM1	Not met	This variant does not lie in a statistically significant hotspot, so available evidence does not support location in a critical mutational hot spot or well-established functional domain without benign variation.	hotspots
PM2	Not met	This variant is not absent from population databases. In gnomAD v2.1 the overall allele frequency is 0.235708 and in gnomAD v4.1 it is 0.180386, both far above the usual rarity threshold of 0.001 for PM2.	gnomad_v2 gnomad_v4
PM3	Not assessed	No data were identified showing this variant in trans with a pathogenic variant in a recessive disorder.
PM4	N/A	This criterion applies to protein length changes from in-frame deletions or insertions or stop-loss variants. This variant is synonymous and does not alter protein length.
PM5	N/A	This criterion applies to a novel missense change at a residue where a different pathogenic missense change has been established. This variant is synonymous and not a missense change.
PM6	Not assessed	No assumed de novo occurrence data were identified for this variant.
PP1	Not assessed	No segregation data were identified showing this variant tracking with disease in affected family members.
PP2	N/A	This criterion applies to missense variants in genes with a low rate of benign missense variation and where missense is a common disease mechanism. This variant is synonymous, not missense.
PP3	Not met	Available computational evidence does not support a deleterious effect. SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, which is below commonly used splice-impact thresholds.	spliceai
PP4	Not assessed	No individual-level phenotype data were identified to show a WT1-related clinical presentation that is highly specific for disease caused by this variant.
PP5	Not assessed	An external clinical database classification was identified, but this criterion was not used as stand-alone evidence for pathogenicity.	clinvar
BA1	Met	Population frequency is well above the benign stand-alone threshold of 0.01. This variant is present in gnomAD v2.1 at AF 0.235708 and in gnomAD v4.1 at AF 0.180386, with East Asian frequencies of 0.697872 and 0.671155, respectively.	gnomad_v2 gnomad_v4
BS1	Met	Population frequency is above the strong benign threshold of 0.003. This variant is present in gnomAD v2.1 at AF 0.235708 and in gnomAD v4.1 at AF 0.180386, both greatly exceeding that threshold.	gnomad_v2 gnomad_v4
BS2	Not assessed	The variant is observed many times in population databases, including numerous homozygotes, but phenotype-confirmed healthy adult observations were not identified for formal BS2 application.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies showing a benign effect of this specific variant were identified.
BS4	Not assessed	No family data were identified showing lack of segregation with disease.
BP1	N/A	This criterion applies to missense variants in genes where truncating variants are primarily pathogenic. This variant is synonymous and not missense.
BP2	Not assessed	No phase data were identified showing this variant in trans with a pathogenic variant for a dominant disorder or in cis with a pathogenic variant.
BP3	N/A	This criterion applies to in-frame deletions or insertions in repetitive regions without known function. This variant is a synonymous single-nucleotide substitution.
BP4	Met	Available computational evidence supports no impact on the gene product or splicing. The variant is synonymous, p.(Arg369=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01.	spliceai
BP5	Not assessed	No evidence was identified for an alternate molecular explanation that would account for the observed phenotype independently of this variant.
BP6	Not assessed	An external clinical database classification was identified, but this criterion was not used as stand-alone evidence for benignity.	clinvar
BP7	Met	This is a synonymous variant, WT1 c.1107A>G (p.Arg369=), and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, supporting no effect on RNA 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.