KMT2A c.5518C>T, p.Pro1840Ser

NM_005933.3:c.5518C>T
COSMIC ID: COSM9177241
Variant of Uncertain Significance (VUS)
The NM_005933.3:c.5518C>T variant in the KMT2A gene is classified as a Variant of Uncertain Significance (VUS). This classification is supported by its extremely low frequency in the population (PM2) and computational predictions suggesting no significant impact on gene function (BP4). Additional evidence is needed to reclassify this variant as either pathogenic or benign.
ACMG/AMP Criteria Applied
PM2 BP4

Genetic Information

Gene & Transcript Details
Gene
KMT2A
Transcript
NM_005933.4
Total Exons
36
Strand
Forward (+)
Reference Sequence
NC_000011.9
Alternative Transcripts
IDStatusDetails
NM_005933.2 Alternative 36 exons | Forward
NM_005933.3 Alternative 36 exons | Forward
Variant Details
HGVS Notation
NM_005933.3:c.5518C>T
Protein Change
P1840S
Location
Exon 19 (Exon 19 of 36)
19
5'Exon Structure (36 total)3'
Functional Consequence
Missense Variant
Related Variants
No evidence of other pathogenic variants at position 1840 in gene KMT2A
Alternate Identifiers
COSM9177241
Variant interpretation based on transcript NM_005933.4

Genome Browser

UCSC Genome Browser hg19/GRCh37
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HGVS InputNM_005933:c.5518C>T
Active Tracks
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Clinical Data

Population Frequency
Global Frequency
0.00319%
Rare
Highest in Population
Ashkenazi Jewish
0.0399%
Low Frequency
Global: 0.00319%
Ashkenazi Jewish: 0.0399%
0%
0.05%
0.1%
1%
5%
10%+
Allele Information
Total: 250742Alt: 8Homozygotes: 0
ACMG Criteria Applied
PM2
This variant is rare in the population (0.003190% MAF).
ClinVar 2025-04-04T21:42:26.788312
Classification
Unknown
Publications (0)
No publication details.
Clinical Statement
COSMIC
COSMIC ID
COSM9177241
Recurrence
1 occurrences
PM1 Criteria
Not Applied
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Functional Impact

Functional Domain
Hotspot Status
Not a hotspot
Domain Summary

This variant is not located in a mutational hotspot or critical domain (0 mutations).

Related Variants in This Domain
No evidence of other pathogenic variants at position 1840 in gene KMT2A
Functional Studies & Therapeutic Relevance
Functional Summary
The variant KMT2A P1840S has not been functionally characterized in the provided sources.

Computational Analysis

Pathogenicity Predictions
REVEL Score
0.326
0.326
Likely Benign0.0
Uncertain (Low)0.2
Uncertain (Med)0.5
Likely Pathogenic0.75
REVEL scores ≥ 0.75 are strong evidence (PP3)
Predictor Consensus
Unknown
PP3 Applied
No
SpliceAI Scores Window: ±500bp
Effect TypeScorePosition
-Acceptor Loss
0.02
-105 bp
-Donor Loss
0.02
30 bp
+Acceptor Gain
0.0
30 bp
+Donor Gain
0.0
-27 bp
High impact (≥0.5)
Medium impact (0.2-0.49)
Low impact (<0.2)

VCEP Guidelines

Applied ACMG/AMP Criteria (VCEP Specific)
PM2
PM2 (Moderate)
According to standard ACMG guidelines: 'PM2 – Absent from controls (or at extremely low frequency if recessive)'. The evidence for this variant shows: The variant has a minor allele frequency (MAF) of 0.00319% in gnomAD, indicating it is extremely rare. Therefore, this criterion meets the requirements because the variant is absent from controls or present at a very low frequency.
BP4
BP4 (Supporting)
According to standard ACMG guidelines: 'BP4 – Multiple lines of computational evidence suggest no impact'. The evidence for this variant shows: In silico predictions indicate a lack of consensus on pathogenicity, with a REVEL score of 0.33 and SpliceAI suggesting minimal impact on splicing. Therefore, this criterion meets the requirements because the computational evidence suggests no significant impact on gene function.