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).1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada in all populations.2 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.3 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.4 Based on the ACMG/AMP 2015 classification framework, a Likely benign classification is appropriate (2 supporting benign criteria, 0 pathogenic criteria).5
KMT2A
Final classification
Likely Benign
KMT2A c.5031G>A · p.Glu1677=
KMT2A
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).
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BP6 supporting, BP7 supporting; combination = 2 supporting benign, which maps to Likely Benign.
Classification rationale
BP6BP7
Likely Benign
KMT2A c.5031G>A
BP6 + BP7
→
Likely Benign
5
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 · 2 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
BP6
supporting
Benign
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 classification: Likely benign by Labcorp Genetics (Invitae). Single submitter with criteria providedthe Sherloc classification framework paper (PMID:28492532) is cited as supporting methodology but does not directly reference this variant.
✓
BP7
supporting
Benign
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.
Synonymous variant p.Glu1677= (c.5031G>A). SpliceAI max delta score 0.00predicting no donor gaindonor loss
Assessed · not applied
Pathogenic
PS2
No de novo evidence has been reported for this variant.
PS3
No functional studies have been identified for this variant.
PS4
No case-control or prevalence data are available to support enrichment of this variant in affected individuals.
PM1
This variant is not located in a statistically significant mutational hotspot or a critical functional domain with established pathogenic enrichment.
PM2
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).
PM6
No de novo observation has been reported for this variant without confirmation of paternity and maternity.
PP1
No segregation data are available for this variant.
PP3
SpliceAI predicts no splicing impact (max delta score 0.00).
PP4
No phenotype or clinical data are available to assess whether the patient's presentation is specific for KMT2A-related disease.
PP5
ClinVar classification for this variant is Likely benign, not pathogenic.
Benign
BA1
This variant is absent from gnomAD; allele frequency does not exceed the 1% BA1 threshold.
BS1
This variant is absent from gnomAD; allele frequency does not exceed the 0.3% BS1 threshold.
BS2
No data are available on observation of this variant in healthy adults with full penetrance expected at an early age.
BS3
No functional studies demonstrating no deleterious effect have been identified for this variant.
BS4
No segregation data are available to demonstrate lack of cosegregation with disease.
BP2
No data are available on whether this variant has been observed in trans with a pathogenic variant in KMT2A.
BP4
BP7 is the more specific ACMG/AMP criterion for synonymous variants with no predicted splicing impact.
BP5
No observation of this variant in a case with an alternate molecular basis for disease has been reported.
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
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Likely benign (1 clinical laboratory). (ClinVarID = 1925883)
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
Triaged references · 1 PMID not cited in assessment
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR