rs1575372815

Variant names:

• chr3-36993246-C-A
• rs1575372815
• ENST00000673673.2:c.-302C>A

Your query was ambiguous. Multiple possible variants found:

• chr3-36993246-C-A
• chr3-36993246-C-T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000673673.2(MLH1):​c.-302C>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000141 in 707,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MLH1 ENST00000673673.2 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.80
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000673673.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	EPM2AIP1	NM_014805.4	MANE Select	c.-169G>T		upstream_gene	N/A	NP_055620.1	Q7L775

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH1	ENST00000673673.2		c.-302C>A		5_prime_UTR	Exon 1 of 18	ENSP00000500979.2	A0A669KAW3
	EPM2AIP1	ENST00000322716.8	TSL:6 MANE Select	c.-169G>T		upstream_gene	N/A	ENSP00000406027.1	Q7L775
	MLH1	ENST00000413740.2	TSL:1	c.-302C>A		upstream_gene	N/A	ENSP00000416476.2	H0Y806

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000141 AC: 1 AN: 707852 Hom.: 0 Cov.: 9 AF XY: 0.00000275 AC XY: 1 AN XY: 363206

⚠️ 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: 17126

American (AMR) AF: 0.00 AC: 0 AN: 20176

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15314

East Asian (EAS) AF: 0.00 AC: 0 AN: 33398

South Asian (SAS) AF: 0.0000190 AC: 1 AN: 52742

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 45994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2524

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 486174

Other (OTH) AF: 0.00 AC: 0 AN: 34404

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Hereditary cancer-predisposing syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.80
DANN	Benign	0.75
PhyloP100		-1.8
PromoterAI		0.057	Neutral

Splicing

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

Other links and lift over

dbSNP: rs1575372815; hg19: chr3-37034737;