Variant classification summary

NM_005933.3:c.2040G>T

KMT2A · NP_005924.2:p.(Ser680=) · NM_005933.3

GRCh37: chr11:118343914 G>T · GRCh38: chr11:118473199 G>T

Gene: KMT2A Transcript: NM_005933.3

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

KMT2A

Transcript

NM_005933.3

Protein

NP_005924.2:p.(Ser680=)

gnomAD AF

1.1157061676236946e-05 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): total allele frequency 0.001% in gnomAD, well below the 0.1% threshold, with no homozygotes.

2

BP7 (Supporting): synonymous p.Ser680= deep in exon 3, with no predicted splice impact (SpliceAI max delta 0.006).

3

VUS: the single supporting plus single supporting combination (PM2 + BP7) meets no benign, likely benign, likely pathogenic, or pathogenic rule under generic ACMG/AMP 2015.

Final determination: Under the generic ACMG/AMP 2015 combination rules applied because no KMT2A VCEP/CSPEC exists, the met criteria (PM2 supporting, BP7 supporting) satisfy no Benign (BA1 alone; 2 BS), Likely Benign (1 BS + 1 BP; 2 BP), Likely Pathogenic, or Pathogenic combination, 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	Not applicable: this is a synonymous (silent) variant, so no null-variant mechanism such as nonsense-mediated decay applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	Not applicable: no amino acid change occurs (p.Ser680=), so there is no altered residue to compare with a known pathogenic variant.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no parental genotyping or trio data were available to confirm a de novo occurrence.	generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional studies of this variant were available to evaluate a deleterious effect.
PS4	Not assessed	Not assessed: no case-control or affected-versus-control enrichment data were available.	generic_acmg_combination_rules clinvar gnomad_v4 gnomad_v2 PMID:28492532
PM1	N/A	Not applicable: a synonymous variant introduces no altered residue to evaluate for a mutational hotspot or critical domain.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD total allele frequency is 0.001%, far below the 0.1% PM2 threshold, with no homozygotes.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
PM3	N/A	Not applicable: KMT2A-related Wiedemann-Steiner syndrome is autosomal dominant, so a recessive in-trans criterion does not apply.	generic_acmg_combination_rules
PM4	N/A	Not applicable: a synonymous variant causes no protein length change, so there is nothing for this criterion to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	Not applicable: no missense change occurs, so there is no residue to compare against a different pathogenic missense.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental genotyping data were available to evaluate assumed de novo status.	generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family or segregation data were available to evaluate co-segregation with disease.	generic_acmg_combination_rules
PP2	N/A	Not applicable: this is a synonymous variant, so the gene's missense-constraint properties do not apply.	generic_acmg_combination_rules
PP3	Not met	Not met: SpliceAI max delta 0.006 is far below the 0.2 splice-altering threshold, and missense predictors do not apply.	spliceai
PP4	Not assessed	Not assessed: no proband-level phenotype data were available to evaluate phenotype specificity.	generic_acmg_combination_rules clinvar PMID:28492532
PP5	Not met	Not met: no ClinVar expert-panel classification exists for this exact variant; only a single-submitter Likely benign assertion.	generic_acmg_combination_rules clinvar
BA1	Not met	Not met: allele frequency 0.001% is orders of magnitude below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not met	Not met: observed allele frequency 0.001% does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS2	Not met	Not met: gnomAD carriers are not phenotype-screened for this early-onset disorder, so unaffected adult status is not demonstrated.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no well-established functional studies showing no damaging effect were available.	spliceai
BS4	Not assessed	Not assessed: no family segregation data were available to demonstrate lack of segregation.	generic_acmg_combination_rules
BP1	N/A	Not applicable: this is a synonymous variant, so the gene's truncating-variant mechanism is not relevant.	generic_acmg_combination_rules
BP2	Not met	Not met: no observation in trans or cis with a pathogenic variant is documented in any source.	generic_acmg_combination_rules
BP3	N/A	Not applicable: this synonymous variant causes no in-frame length change in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: no independent BP4 prediction exists beyond the SpliceAI result already applied under BP7.	spliceai
BP5	Not assessed	Not assessed: no affected carrier is reported in whom an alternate molecular basis could be documented.	generic_acmg_combination_rules clinvar PMID:28492532
BP6	Not met	Not met: no ClinVar expert-panel benign assertion exists; a single-submitter Likely benign label does not trigger BP6.	generic_acmg_combination_rules clinvar
BP7	Met	Met (supporting): synonymous p.Ser680= deep in exon 3 with SpliceAI max delta 0.006, well below the 0.2 splice-altering threshold.	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.