Genetic Variant MLH1:c.791-488A>G (chr3-37017018-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_000249.4(MLH1):c.791-488A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.433 in 800,902 control chromosomes in the GnomAD database, including 79,834 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.45 ( 16014 hom., cov: 32)

Exomes 𝑓: 0.43 ( 63820 hom. )

Consequence

MLH1
NM_000249.4 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.32

Publications

10 publications found

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:

RPL29P11 (HGNC:36905): (ribosomal protein L29 pseudogene 11)

RPL29P11 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-1.03).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.483 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH1	NM_000249.4 link	c.791-488A>G		intron_variant	Intron 9 of 18	ENST00000231790.8	NP_000240.1	P40692-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH1	ENST00000231790.8 link	c.791-488A>G		intron_variant	Intron 9 of 18	1	NM_000249.4	ENSP00000231790.3		P40692-1

Frequencies

GnomAD3 genomes

AF:

0.448

AC:

68091

AN:

151884

Hom.:

16003

Cov.:

show subpopulations

Gnomad AFR

AF:

0.468

Gnomad AMI

AF:

0.570

Gnomad AMR

AF:

0.445

Gnomad ASJ

AF:

0.430

Gnomad EAS

AF:

0.0772

Gnomad SAS

AF:

0.247

Gnomad FIN

AF:

0.401

Gnomad MID

AF:

0.408

Gnomad NFE

AF:

0.487

Gnomad OTH

AF:

0.437

GnomAD4 exome

AF:

0.429

AC:

278593

AN:

648900

Hom.:

63820

Cov.:

AF XY:

0.423

AC XY:

147570

AN XY:

348472

show subpopulations

African (AFR)

AF:

0.469

AC:

8150

AN:

17364

American (AMR)

AF:

0.393

AC:

13804

AN:

35146

Ashkenazi Jewish (ASJ)

AF:

0.439

AC:

7949

AN:

18094

East Asian (EAS)

AF:

0.118

AC:

4270

AN:

36172

South Asian (SAS)

AF:

0.268

AC:

16529

AN:

61764

European-Finnish (FIN)

AF:

0.408

AC:

14569

AN:

35724

Middle Eastern (MID)

AF:

0.397

AC:

984

AN:

2478

European-Non Finnish (NFE)

AF:

0.485

AC:

197933

AN:

408494

Other (OTH)

AF:

0.428

AC:

14405

AN:

33664

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

8140

16280

24420

32560

40700

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2204

4408

6612

8816

11020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.448

AC:

68132

AN:

152002

Hom.:

16014

Cov.:

AF XY:

0.439

AC XY:

32641

AN XY:

74294

show subpopulations

African (AFR)

AF:

0.467

AC:

19356

AN:

41436

American (AMR)

AF:

0.445

AC:

6801

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.430

AC:

1492

AN:

3466

East Asian (EAS)

AF:

0.0772

AC:

399

AN:

5170

South Asian (SAS)

AF:

0.247

AC:

1191

AN:

4820

European-Finnish (FIN)

AF:

0.401

AC:

4226

AN:

10534

Middle Eastern (MID)

AF:

0.388

AC:

114

AN:

294

European-Non Finnish (NFE)

AF:

0.487

AC:

33123

AN:

67982

Other (OTH)

AF:

0.432

AC:

912

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

1899

3798

5697

7596

9495

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

606

1212

1818

2424

3030

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.464

Hom.:

3988

Bravo

AF:

0.451

Asia WGS

AF:

0.210

AC:

734

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-1.0

CADD

Benign

0.57

(source)

DANN

Benign

0.49

PhyloP100

-2.3

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over