Variant 3-37025608-ATTTTTTTTT-ATTTTTTT details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_StrongBS1BS2

The NM_000249.4(MLH1):c.1039-9_1039-8del variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00648 in 305,654 control chromosomes in the GnomAD database, including 31 homozygotes. Variant has been reported in ClinVar as Likely benign (★★). There are indicators that this mutation may affect the branch point..

Frequency

Genomes: 𝑓 0.00017 ( 0 hom., cov: 0)

Exomes 𝑓: 0.0077 ( 31 hom. )

Consequence

MLH1
NM_000249.4 intron

Scores

Not classified

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.431

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 -16 ACMG points.

BP6

Variant 3-37025608-ATT-A is Benign according to our data. Variant chr3-37025608-ATT-A is described in ClinVar as [Likely_benign]. Clinvar id is 433863.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00767 (1974/257382) while in subpopulation AMR AF= 0.0142 (18/1268). AF 95% confidence interval is 0.0108. There are 31 homozygotes in gnomad4_exome. There are 956 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 31 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1039-9_1039-8del		intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1039-9_1039-8del		intron_variant		1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.000166

AC:

AN:

48284

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000250

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000481

Gnomad SAS

AF:

0.000745

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000115

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00810

AC:

113

AN:

13956

Hom.:

AF XY:

0.00536

AC XY:

AN XY:

8400

show subpopulations

Gnomad AFR exome

AF:

0.0746

Gnomad AMR exome

AF:

0.0144

Gnomad ASJ exome

AF:

0.00309

Gnomad EAS exome

AF:

0.0556

Gnomad SAS exome

AF:

0.00830

Gnomad FIN exome

AF:

0.00299

Gnomad NFE exome

AF:

0.00801

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00767

AC:

1974

AN:

257382

Hom.:

AF XY:

0.00748

AC XY:

956

AN XY:

127796

show subpopulations

Gnomad4 AFR exome

AF:

0.00839

Gnomad4 AMR exome

AF:

0.0142

Gnomad4 ASJ exome

AF:

0.00479

Gnomad4 EAS exome

AF:

0.00564

Gnomad4 SAS exome

AF:

0.0133

Gnomad4 FIN exome

AF:

0.0199

Gnomad4 NFE exome

AF:

0.00745

Gnomad4 OTH exome

AF:

0.00851

GnomAD4 genome

AF:

0.000166

AC:

AN:

48272

Hom.:

Cov.:

AF XY:

0.000233

AC XY:

AN XY:

21492

show subpopulations

Gnomad4 AFR

AF:

0.000249

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000484

Gnomad4 SAS

AF:

0.000749

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000115

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Department of Pathology and Laboratory Medicine, Sinai Health System	Mar 21, 2016	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	Jul 31, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

La Branchor

0.24

BranchPoint Hunter

2.0

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