NM_005933.3:c.7362T>C

KMT2A · NP_005924.2:p.(Thr2454=) · NM_005933.3

GRCh37: chr11:118373978 T>C · GRCh38: chr11:118503263 T>C

Gene: KMT2A Transcript: NM_005933.3

Final call

Likely Benign

PM2 supporting BP4 supporting BP7 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Thr2454=)

gnomAD AF

1.2391880839673845e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005933.3:c.7362T>C is a synonymous variant (p.Thr2454=) in KMT2A. KMT2A loss-of-function variants cause Wiedemann-Steiner syndrome (autosomal dominant).

This variant is present at extremely low frequency in population databases (gnomAD v2.1: 2/282,756 alleles, AF=7.07e-06; gnomAD v4.1: 2/1,613,960 alleles, AF=1.24e-06), meeting PM2 at supporting level.

SpliceAI predicts no splice impact (max delta=0.0; all four delta scores at 0.0), supporting a benign interpretation under BP4 and BP7.

No pathogenic in silico predictions are available; REVEL and BayesDel scores were not found for this variant. No computational evidence supports a deleterious effect (PP3 not met).

The variant is absent from ClinVar and no literature reports this specific variant. OncoKB lists classification as 'Unknown Oncogenic Effect' with no supporting evidence.

Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting pathogenic) is outweighed by BP4 (supporting benign) and BP7 (supporting benign), yielding a classification of Likely Benign (2 supporting benign criteria).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting 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	N/A	NM_005933.3:c.7362T>C is a synonymous variant (p.Thr2454=) that does not fall into a null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to synonymous variants.	pvs1_variant_assessment pvs1_gene_context
PS1	N/A	PS1 requires a same amino acid change as an established pathogenic variant. This variant is synonymous (p.Thr2454=) and produces no amino acid change.
PS2	Not assessed	No de novo data available. Literature search returned no PMIDs and no full-text publications were identified for this variant.
PS3	Not assessed	No functional studies identified. Literature search returned no PMIDs; OncoKB lists classification as 'Unknown Oncogenic Effect' with no variant-specific functional evidence.	oncokb
PS4	Not assessed	No case-control or statistical enrichment data available. This variant is absent from ClinVar and has no published case reports.
PS5	N/A	Variant is absent from ClinVar; no expert panel or reputable source has classified this variant as pathogenic.	clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot and is not located in a well-established critical functional domain without benign variation.
PM2	Met	This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=7.07e-06 (2/282,756 alleles, 0 homozygotes) and gnomAD v4.1 AF=1.24e-06 (2/1,613,960 alleles, 0 homozygotes), well below the PM2 threshold of <0.1%. Absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different missense change at the same residue as an established pathogenic missense variant. This variant is synonymous (p.Thr2454=) and causes no amino acid change; PM5 candidate harvesting was unable to parse missense residue context.	pm5_candidates
PM6	Not assessed	No de novo data available. Literature search returned no PMIDs for this variant.
PP1	Not assessed	No co-segregation data available. No family studies or published pedigrees were identified for this variant.
PP2	N/A	PP2 applies to missense variants in genes where missense variants are a common mechanism and benign missense variation is low. This variant is synonymous (p.Thr2454=), not missense.
PP3	Not met	No pathogenic in silico predictions are available. REVEL and BayesDel scores were not found for this variant. SpliceAI predicts no splice impact (max delta=0.0). No computational evidence supports a deleterious effect.	spliceai
PP4	Not assessed	No patient phenotype or clinical data were provided for assessment. No published case reports describing this variant in affected individuals were identified.
PP5	Not met	No reputable source has classified this variant as pathogenic. The variant is absent from ClinVar. OncoKB reports classification as 'Unknown Oncogenic Effect' which does not constitute an assertion of pathogenicity.	clinvar oncokb
BA1	Not met	gnomAD allele frequency is far below the BA1 threshold of >1%. Highest observed population frequency is 1.55e-05 (NFE, v2.1) and overall AF is 7.07e-06 in v2.1 and 1.24e-06 in v4.1.	gnomad_v2 gnomad_v4
BS1	Not met	gnomAD allele frequency is far below the BS1 threshold of >0.3%. Highest population AF is 0.00155% (NFE, v2.1).	gnomad_v2 gnomad_v4
BS2	Not assessed	No data available for observation in healthy adult controls. While the variant is observed in 2 individuals in gnomAD (a population database enriched for apparently healthy individuals), this alone is insufficient for BS2 without detailed phenotype confirmation.
BS3	Not assessed	No functional studies demonstrating no deleterious effect have been identified. No literature or experimental data available for this variant.
BS4	Not assessed	No segregation data available. No family studies demonstrating lack of segregation with disease were identified.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are a known mechanism of disease. This variant is synonymous (p.Thr2454=), not missense.
BP2	Not assessed	No data available on observation in trans with a pathogenic variant in this autosomal dominant disorder.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this is a single-nucleotide substitution.
BP4	Met	Multiple lines of computational evidence suggest no impact. SpliceAI predicts no splice alteration (max delta=0.0; all four delta scores at 0.0). This is a synonymous variant with no predicted effect on splicing.	spliceai
BP5	Not assessed	No data available on an alternative molecular basis for disease in cases harboring this variant.
BP6	Not assessed	Variant is absent from ClinVar; no reputable source has classified this variant as benign.	clinvar
BP7	Met	This is a synonymous variant (p.Thr2454=) with no predicted splice impact. SpliceAI predicts no alteration to splice consensus sequences or creation of a new splice site (max delta=0.0; all four delta scores at 0.0). Nucleotide conservation data are not available; however, the SpliceAI prediction provides strong evidence for no splicing effect.	spliceai
PM3	N/A	PM3 applies to recessive disorders; KMT2A-associated Wiedemann-Steiner syndrome is autosomal dominant. No recessive disease context identified.
PM4	N/A	PM4 applies to protein length changes from in-frame indels, stop-loss, or initiation codon variants. This is a synonymous single-nucleotide substitution with no protein length alteration.

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