rs1558528

chr3-37015499-C-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000249.4(MLH1):c.790+955C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.406 in 152,124 control chromosomes in the GnomAD database, including 13,142 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency: Genomes: 𝑓 0.41 (13142 hom., cov: 33)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:1
• Conservation: PhyloP100: -0.806

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-37015499-C-A is Benign according to our data. Variant chr3-37015499-C-A is described in ClinVar as [Benign]. Clinvar id is 90366.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37015499-C-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.790+955C>A		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.790+955C>A		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.407 AC: 61800 AN: 152006 Hom.: 13137 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.536

Gnomad AMR AF: 0.413

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.0778

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.366

Gnomad MID AF: 0.373

Gnomad NFE AF: 0.458

Gnomad OTH AF: 0.391

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.406 AC: 61823 AN: 152124 Hom.: 13142 Cov.: 33 AF XY: 0.399 AC XY: 29641 AN XY: 74372

Gnomad4 AFR AF: 0.388

Gnomad4 AMR AF: 0.414

Gnomad4 ASJ AF: 0.410

Gnomad4 EAS AF: 0.0778

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.366

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.387

Alfa AF: 0.424 Hom.: 1701

Bravo AF: 0.408

Asia WGS AF: 0.197 AC: 690 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: reviewed by expert panel

Submissions by phenotype

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
Cadd	Benign	1.0
Dann	Benign	0.74

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs1558528; hg19: chr3-37056990;