rs11129748

chr3-37025559-A-Gchr3-37025559-A-T

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.1039-78A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.45 in 709,402 control chromosomes in the GnomAD database, including 78,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10133 hom., cov: 24)
  • Exomes 𝑓: 0.47 (68415 hom.)
• Consequence: MLH1 NM_000249.4 intron
• Clinical Significance: Benign reviewed by expert panel B:3
• Conservation: PhyloP100: -1.10

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=-0.95).
• BP6: Variant 3-37025559-A-G is Benign according to our data. Variant chr3-37025559-A-G is described in ClinVar as [Benign]. Clinvar id is 89625.Status of the report is reviewed_by_expert_panel, 3 stars. Variant chr3-37025559-A-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.451 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4	c.1039-78A>G		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8	c.1039-78A>G		intron_variant		1	NM_000249.4	P1

Frequencies

GnomAD3 genomes AF: 0.360 AC: 50413 AN: 139848 Hom.: 10131 Cov.: 24

Gnomad AFR AF: 0.217

Gnomad AMI AF: 0.537

Gnomad AMR AF: 0.398

Gnomad ASJ AF: 0.408

Gnomad EAS AF: 0.0780

Gnomad SAS AF: 0.225

Gnomad FIN AF: 0.375

Gnomad MID AF: 0.368

Gnomad NFE AF: 0.456

Gnomad OTH AF: 0.358

GnomAD4 exome AF: 0.472 AC: 268833 AN: 569542 Hom.: 68415 AF XY: 0.469 AC XY: 133530 AN XY: 284888

Gnomad4 AFR exome AF: 0.199

Gnomad4 AMR exome AF: 0.396

Gnomad4 ASJ exome AF: 0.434

Gnomad4 EAS exome AF: 0.123

Gnomad4 SAS exome AF: 0.292

Gnomad4 FIN exome AF: 0.424

Gnomad4 NFE exome AF: 0.498

Gnomad4 OTH exome AF: 0.415

GnomAD4 genome AF: 0.360 AC: 50411 AN: 139860 Hom.: 10133 Cov.: 24 AF XY: 0.353 AC XY: 23806 AN XY: 67346

Gnomad4 AFR AF: 0.217

Gnomad4 AMR AF: 0.399

Gnomad4 ASJ AF: 0.408

Gnomad4 EAS AF: 0.0779

Gnomad4 SAS AF: 0.225

Gnomad4 FIN AF: 0.375

Gnomad4 NFE AF: 0.456

Gnomad4 OTH AF: 0.355

Alfa AF: 0.375 Hom.: 1651

Bravo AF: 0.347

Asia WGS AF: 0.180 AC: 621 AN: 3424

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: reviewed by expert panel

Submissions by phenotype

not specified Benign:1

Benign, no assertion criteria provided

research

Mayo Clinic Laboratories, Mayo Clinic

-

- -

Lynch syndrome Benign:1

Benign, reviewed by expert panel

research

International Society for Gastrointestinal Hereditary Tumours (InSiGHT)

Sep 05, 2013

MAF >1% -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
Cadd	Benign	0.013
Dann	Benign	0.54

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: rs11129748; hg19: chr3-37067050;