NM_005933.3:c.8878G>T

KMT2A · NP_005924.2:p.(Val2960Leu) · NM_005933.3

GRCh37: chr11:118375494 G>T · GRCh38: chr11:118504779 G>T

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Val2960Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005933.3:c.8878G>T (p.Val2960Leu) is a missense variant in exon 27 of KMT2A.

This variant is absent from gnomAD v2.1 and v4.1 population databases (PM2_Supporting).

Multiple lines of computational evidence predict no deleterious effect: REVEL score 0.178, BayesDel score -0.147545, and SpliceAI max delta 0.00 (BP4_Supporting).

The variant is absent from ClinVar; no pathogenic or benign classification has been assigned by any clinical submitter.

No functional studies, segregation data, de novo observations, or case reports were identified for this specific variant in the literature.

Under generic ACMG/AMP 2015 combination rules, PM2_Supporting and BP4_Supporting are in opposing directions and do not combine to reach a conclusive classification. The variant is classified as a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	N/A	NM_005933.3:c.8878G>T is a missense variant (p.Val2960Leu). PVS1 is reserved for null variants (nonsense, frameshift, or canonical ±1,2 splice consensus). This variant does not fall into any of those categories.	pvs1_generic_framework pvs1_variant_assessment
PS1	N/A	No known pathogenic variant at the same amino acid position (p.Val2960) with the same amino acid change is available for comparison. The variant is absent from ClinVar, and no comparator exists to support that a different nucleotide change at this position resulting in the same missense change has been established as pathogenic.	clinvar pm5_candidates
PS2	Not met	No evidence of de novo occurrence for NM_005933.3:c.8878G>T. No case reports, cohort studies, or clinical testing data confirming de novo status were identified in the literature or ClinVar.	clinvar
PS3	Not met	No well-established in vitro or in vivo functional studies demonstrating a damaging effect on the gene or gene product were identified for this variant. OncoKB reports Unknown Oncogenic Effect. REVEL score of 0.178 and BayesDel score of -0.147545 are below thresholds for predicting deleterious impact.	oncokb revel bayesdel
PS4	Not met	The prevalence of this variant in affected individuals has not been established. The variant is absent from ClinVar and no case-control studies or affected cohort data are available to demonstrate enrichment in cases over controls.	clinvar
PS5	N/A	No de novo report exists for this variant (with both maternity and paternity confirmed). PS5 requires a reported de novo observation in the literature.
PM1	Not met	The variant does not lie in a known mutational hotspot or a critical functional domain with a statistically significant enrichment of pathogenic variation. Residue p.Val2960 is not listed as a significant hotspot by Cancer Hotspots, and ClinVar does not show pathogenic variants clustered at this position.	clinvar
PM2	Met	This variant is absent from gnomAD v2.1 (exome) and gnomAD v4.1 (exome) population databases, consistent with PM2 under generic ACMG/AMP 2015 interpretation.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No other pathogenic missense variant at the same amino acid residue (p.Val2960) was identified in ClinVar. PM5 requires a different pathogenic missense change at the same residue as supporting evidence, which is not available.	pm5_candidates
PM6	Not met	No confirmed de novo observation for this variant was identified in the literature. PM6 requires a de novo observation with confirmed maternity and paternity, which is not available for NM_005933.3:c.8878G>T.
PP1	Not met	No cosegregation data with disease in multiple affected family members is available for this variant.
PP2	Not met	HCI prior is not supported for the KMT2A gene (gene_not_supported). No gene-specific missense constraint metric is available to determine whether missense variants are a common mechanism of disease for this gene.
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.178 (below the 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00).	revel bayesdel spliceai
PP4	Not met	No patient phenotype data specific to this variant are available. No case reports describe the clinical presentation of an individual harboring NM_005933.3:c.8878G>T to allow assessment of phenotypic fit with KMT2A-related Wiedemann-Steiner syndrome.
PP5	Not met	The variant is absent from ClinVar. No reputable source (clinical diagnostic laboratory, expert panel) has classified this variant as pathogenic.	clinvar
BA1	Not met	The variant is absent from gnomAD population databases. Allele frequency is not >1%, which is the threshold for BA1.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from gnomAD population databases. Allele frequency is not >0.3%, which is the threshold for BS1.	gnomad_v2 gnomad_v4
BS2	Not met	No data are available on healthy adult controls carrying this variant. BS2 requires observation in healthy adults for a fully penetrant dominant disorder, which has not been reported for NM_005933.3:c.8878G>T.
BS3	Not met	No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing have been identified for this variant. While in silico predictors are benign-leaning, BS3 requires experimental functional evidence, which is absent.	oncokb
BS4	Not met	No segregation data demonstrating lack of cosegregation with disease are available for this variant.
BP1	N/A	BP1 applies to missense variants in genes where only truncating variants are established as disease-causing. KMT2A-associated Wiedemann-Steiner syndrome is caused by both truncating and missense variants; therefore, a missense variant in KMT2A does not meet BP1 criteria.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in a gene associated with a recessive disorder has been reported.
BP4	Met	Multiple lines of computational evidence predict no deleterious impact. REVEL score is 0.178 (below 0.5 pathogenic threshold), BayesDel score is -0.147545 (negative score indicates benign), and SpliceAI predicts no splice impact (max delta score 0.00).	revel bayesdel spliceai
BP5	Not met	No alternative molecular basis for disease has been identified in a case harboring this variant. BP5 requires a stronger pathogenic variant explaining the phenotype in the same individual, which has not been reported for this variant.
BP6	Not met	No reputable source classifies this variant as benign or likely benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact. NM_005933.3:c.8878G>T is a missense variant (p.Val2960Leu) and is not eligible for BP7.
BP3	N/A	This variant is a substitution, not an in-frame insertion/deletion in a repetitive region.
PM3	N/A	KMT2A-associated disease (Wiedemann-Steiner syndrome) is an autosomal dominant disorder. PM3 applies to recessive disorders.
PM4	N/A	This variant is a substitution, not a protein-length-altering variant (in-frame deletion/insertion or stop-loss).

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.