NM_005933.3:c.5031G>A

KMT2A · NP_005924.2:p.(Glu1677=) · NM_005933.3

GRCh37: chr11:118363807 G>A · GRCh38: chr11:118493092 G>A

Gene: KMT2A Transcript: NM_005933.3

Final call

Likely Benign

BP6 supporting BP7 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Glu1677=)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_005933.3:c.5031G>A is a synonymous variant (p.Glu1677=) in KMT2A with no predicted effect on splicing (SpliceAI max delta score 0.00).

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada in all populations.

This variant has been classified as Likely benign by a reputable clinical diagnostic laboratory (Labcorp Genetics/Invitae) in ClinVar (variation ID 1925883), though the underlying evidence is not publicly available for independent review.

Two supporting benign criteria are met: BP6 (reputable source classifies as benign) and BP7 (synonymous variant with no predicted splicing impact). No pathogenic criteria are met.

Based on the ACMG/AMP 2015 classification framework, a Likely benign classification is appropriate (2 supporting benign criteria, 0 pathogenic 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	Synonymous variant (p.Glu1677=) with no predicted splicing impact; PVS1 applies only to null variants (nonsense, frameshift, canonical ±1,2 splice, initiation codon, or exon deletion).	pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	Synonymous variant with no amino acid change; PS1 requires a different nucleotide substitution at the same codon producing the same missense change, which is not applicable to synonymous variants.
PS2	Not met	No de novo evidence has been reported for this variant.
PS3	Not met	No functional studies have been identified for this variant.
PS4	Not met	No case-control or prevalence data are available to support enrichment of this variant in affected individuals.
PS5	N/A	Not a standard ACMG/AMP 2015 criterion; no applicable evidence to assess under this category.
PM1	Not met	This variant is not located in a statistically significant mutational hotspot or a critical functional domain with established pathogenic enrichment.
PM2	Not met	Although absent from gnomAD v2.1, v4.1, and gnomAD-Canada, this is a synonymous variant with no predicted functional impact (SpliceAI max delta 0.00). PM2 is not appropriately applied to synonymous variants absent evidence of a functional consequence.	gnomad_v2 gnomad_v4 gnomad_canada spliceai
PM5	N/A	Synonymous variant (p.Glu1677=) produces no amino acid change; PM5 requires a different pathogenic missense change at the same residue, which is not applicable to synonymous variants.	pm5_candidates
PM6	Not met	No de novo observation has been reported for this variant without confirmation of paternity and maternity.
PP1	Not met	No segregation data are available for this variant.
PP2	N/A	Synonymous variant, not missense. PP2 applies specifically to missense variants in genes where missense variants are a common mechanism of disease and benign missense variation is rare.
PP3	Not met	SpliceAI predicts no splicing impact (max delta score 0.00). No deleterious in silico predictions are available for this synonymous variant.	spliceai
PP4	Not met	No phenotype or clinical data are available to assess whether the patient's presentation is specific for KMT2A-related disease.
PP5	Not met	ClinVar classification for this variant is Likely benign, not pathogenic. PP5 requires a reputable source to report the variant as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD; allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD; allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available on observation of this variant in healthy adults with full penetrance expected at an early age.
BS3	Not met	No functional studies demonstrating no deleterious effect have been identified for this variant.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease.
BP1	N/A	Synonymous variant, not missense. BP1 applies specifically to missense variants in genes where primarily truncating variants cause disease. BP7 is the specific criterion for synonymous variants.
BP2	Not met	No data are available on whether this variant has been observed in trans with a pathogenic variant in KMT2A.
BP3	N/A	In-frame deletions/insertions in repetitive regions are not applicable; this is a single nucleotide synonymous substitution.
BP4	Not met	BP7 is the more specific ACMG/AMP criterion for synonymous variants with no predicted splicing impact. Applying both BP4 and BP7 would double-count the same SpliceAI evidence. BP7 is applied instead.	spliceai
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Met	This variant has been classified as Likely benign by Labcorp Genetics (formerly Invitae), a reputable clinical diagnostic laboratory (ClinVar variation ID 1925883, SCV002959647, criteria provided, single submitter). The underlying evidence is not available for independent evaluation.	clinvar
BP7	Met	This is a synonymous variant (p.Glu1677=) with SpliceAI predicting no impact on splicing (max delta score 0.00), consistent with no effect on the gene product.	spliceai
PM3	N/A	Skipped per user instruction.
PM4	N/A	Skipped per user instruction. Additionally, this variant is a single nucleotide synonymous substitution, not an 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.