Variant rs11129748 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign reviewed by expert panel B:4

Conservation

PhyloP100: -1.10

Variant links:

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]

MLH1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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 linkuse as main transcript	c.1039-78A>G		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1039-78A>G		intron_variant		1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.360

AC:

50413

AN:

139848

Hom.:

10131

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.353

AC XY:

23806

AN XY:

67346

show subpopulations

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:4

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

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% -

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over