Variant rs730881737 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 1P and 0B. PP3

The NM_000249.4(MLH1):c.1039-3C>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00024 ( 0 hom., cov: 24)

Exomes 𝑓: 0.0063 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MLH1
NM_000249.4 splice_region, splice_polypyrimidine_tract, intron

Scores

Splicing: ADA: 0.9654

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.31

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 Uncertain_significance. Variant got 1 ACMG points.

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. Scorers claiming Uncertain: max_spliceai. No scorers claiming Benign.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH1	NM_000249.4 linkuse as main transcript	c.1039-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000231790.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH1	ENST00000231790.8 linkuse as main transcript	c.1039-3C>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000249.4	P1	P40692-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

103528

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.000298

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000351

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00160

Gnomad SAS

AF:

0.000906

Gnomad FIN

AF:

0.000489

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000895

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000196

AC:

AN:

152942

Hom.:

AF XY:

0.00

AC XY:

AN XY:

86352

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000122

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000258

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.00632

AC:

5119

AN:

809456

Hom.:

Cov.:

AF XY:

0.00589

AC XY:

2399

AN XY:

407168

show subpopulations

Gnomad4 AFR exome

AF:

0.0102

Gnomad4 AMR exome

AF:

0.00167

Gnomad4 ASJ exome

AF:

0.00420

Gnomad4 EAS exome

AF:

0.00461

Gnomad4 SAS exome

AF:

0.00456

Gnomad4 FIN exome

AF:

0.000763

Gnomad4 NFE exome

AF:

0.00687

Gnomad4 OTH exome

AF:

0.00625

GnomAD4 genome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.000241

AC:

AN:

103556

Hom.:

Cov.:

AF XY:

0.000167

AC XY:

AN XY:

47974

show subpopulations

Gnomad4 AFR

AF:

0.000298

Gnomad4 AMR

AF:

0.000350

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00161

Gnomad4 SAS

AF:

0.000909

Gnomad4 FIN

AF:

0.000489

Gnomad4 NFE

AF:

0.0000895

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 17, 2017

The c.1039-3C>A intronic variant results from a C to A substitution 3 nucleotides upstream from coding exon 12 in the MLH1 gene. This nucleotide position is well conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to weaken the efficiency of the native splice acceptor site; however, direct evidence is unavailable. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.38

Cadd

Benign

Dann

Benign

0.84

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.97

dbscSNV1_RF

Pathogenic

0.74

SpliceAI score (max)

0.32

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.32

Position offset: 3

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