3-36993268-A-T

Variant names:

• chr3-36993268-A-T
• rs876658200
• ENST00000673673.2:c.-280A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000673673.2(MLH1):​c.-280A>T variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000163 in 614,932 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000016 (0 hom.)
• Consequence: MLH1 ENST00000673673.2 5_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.57
• Publications: 0 publications found

Genes affected

MLH1 (HGNC:7127): (mutL homolog 1) The protein encoded by this gene can heterodimerize with mismatch repair endonuclease PMS2 to form MutL alpha, part of the DNA mismatch repair system. When MutL alpha is bound by MutS beta and some accessory proteins, the PMS2 subunit of MutL alpha introduces a single-strand break near DNA mismatches, providing an entry point for exonuclease degradation. The encoded protein is also involved in DNA damage signaling and can heterodimerize with DNA mismatch repair protein MLH3 to form MutL gamma, which is involved in meiosis. This gene was identified as a locus frequently mutated in hereditary nonpolyposis colon cancer (HNPCC). [provided by RefSeq, Aug 2017]

EPM2AIP1 (HGNC:19735): (EPM2A interacting protein 1) The EPM2A gene, which encodes laforin, is mutated in an autosomal recessive form of adolescent progressive myoclonus epilepsy. The protein encoded by this gene binds to laforin, but its function is not known. This gene is intronless. [provided by RefSeq, Oct 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4	c.-280A>T		upstream_gene_variant		ENST00000231790.8	NP_000240.1
EPM2AIP1	NM_014805.4	c.-191T>A		upstream_gene_variant		ENST00000322716.8	NP_055620.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8	c.-280A>T		upstream_gene_variant		1	NM_000249.4	ENSP00000231790.3
EPM2AIP1	ENST00000322716.8	c.-191T>A		upstream_gene_variant		6	NM_014805.4	ENSP00000406027.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000163 AC: 1 AN: 614932 Hom.: 0 Cov.: 8 AF XY: 0.00 AC XY: 0 AN XY: 318386

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 15318

American (AMR) AF: 0.00 AC: 0 AN: 19942

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14830

East Asian (EAS) AF: 0.00 AC: 0 AN: 32250

South Asian (SAS) AF: 0.00 AC: 0 AN: 50436

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45016

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2312

European-Non Finnish (NFE) AF: 0.00000248 AC: 1 AN: 403558

Other (OTH) AF: 0.00 AC: 0 AN: 31270

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	20
DANN	Benign	0.97
PhyloP100		3.6
PromoterAI		-0.071	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs876658200; hg19: chr3-37034759;