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).1 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.2 SpliceAI predicts no splice impact (max delta=0.0; all four delta scores at 0.0), supporting a benign interpretation under BP4 and BP7.3 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).4 The variant is absent from ClinVar and no literature reports this specific variant. OncoKB lists classification as 'Unknown Oncogenic Effect' with no supporting evidence.5 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).6
KMT2A
Final classification
Likely Benign
PM2BP4BP7
KMT2A
c.7362T>C
p.Thr2454=
This variant
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
Classification rationale
PM2
BP4BP7
Likely Benign
KMT2A c.7362T>C
PM2 + BP4 + BP7
→
Likely Benign
1
pvs1_gene_context
6
generic_acmg_combination_rules
Gene diagram
· NM_005933.3 · variants mapped to exon structure
KMT2A
NM_005933.3
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 17 assessed
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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 v2.1: 2/282756 alleles (AF=0.0007%)highest in NFE subpopulation (AF=0.00155%)
✓
BP4
supporting
Benign
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 max delta=0.0 (DS_AG=0.0DS_AL=0.0DS_DG=0.0
✓
BP7
supporting
review
Benign
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.
Synonymous variant p.(Thr2454=)no amino acid changeSpliceAI max delta=0.0
Assessed · not applied
· 5 not met · 12 not assessed
Pathogenic
PS2
No de novo data available.
PS3
No functional studies identified.
PS4
No case-control or statistical enrichment data available.
PM1
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.
PM6
No de novo data available.
PP1
No co-segregation data available.
PP3
No pathogenic in silico predictions are available.
PP4
No patient phenotype or clinical data were provided for assessment.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
gnomAD allele frequency is far below the BA1 threshold of >1%.
BS1
gnomAD allele frequency is far below the BS1 threshold of >0.3%.
BS2
No data available for observation in healthy adult controls.
BS3
No functional studies demonstrating no deleterious effect have been identified.
BS4
No segregation data available.
BP2
No data available on observation in trans with a pathogenic variant in this autosomal dominant disorder.
BP5
No data available on an alternative molecular basis for disease in cases harboring this variant.
BP6
Variant is absent from ClinVar; no reputable source has classified this variant as benign.
N/A · 8
PVS1 · PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.23919e-06; MAF= 0.00012%, 2/1613960 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69488e-06; MAF= 0.00017%, 2/1180022 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
v2.1
This variant is present in gnomAD v2.1 (AF= 7.07324e-06; MAF= 0.00071%, 2/282756 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.54909e-05; MAF= 0.00155%, 2/129108 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00012%
· 2 / 1,613,960
0 hom · FAF 2.8e-05%
0 hom · FAF 2.8e-05%
European (non-Finnish) 2 / 1,180,022 |
0.00017% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.00071%
· 2 / 282,756
0 hom
0 hom
European (non-Finnish) 2 / 129,108 |
0.0015% |
+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
Unknown Oncogenic Effect
OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links