NM_001040108.2:c.2476A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001040108.2(MLH3):c.2476A>G(p.Asn826Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.998 in 1,614,180 control chromosomes in the GnomAD database, including 803,856 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in ClinVar.

Frequency

Genomes: 𝑓 0.99 ( 74524 hom., cov: 32)

Exomes 𝑓: 1.0 ( 729332 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11

Conservation

PhyloP100: 0.319

Publications

45 publications found

Variant links:

Genes affected

MLH3 (HGNC:7128): (mutL homolog 3) This gene is a member of the MutL-homolog (MLH) family of DNA mismatch repair (MMR) genes. MLH genes are implicated in maintaining genomic integrity during DNA replication and after meiotic recombination. The protein encoded by this gene functions as a heterodimer with other family members. Somatic mutations in this gene frequently occur in tumors exhibiting microsatellite instability, and germline mutations have been linked to hereditary nonpolyposis colorectal cancer type 7 (HNPCC7). Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. [provided by RefSeq, Jul 2008]

MLH3 Gene-Disease associations (from GenCC):

colorectal cancer, hereditary nonpolyposis, type 7
Inheritance: AD, AR Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, ClinGen, Laboratory for Molecular Medicine

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6601552E-6).

BP6

Variant 14-75047180-T-C is Benign according to our data. Variant chr14-75047180-T-C is described in ClinVar as Benign. ClinVar VariationId is 257251.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 13	NP_001035197.1
	MLH3	NM_014381.3		c.2476A>G	p.Asn826Asp	missense	Exon 2 of 12	NP_055196.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MLH3	ENST00000355774.7	TSL:5 MANE Select	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 13	ENSP00000348020.2
MLH3	ENST00000380968.6	TSL:1	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 12	ENSP00000370355.3
MLH3	ENST00000556257.5	TSL:5	c.2476A>G	p.Asn826Asp	missense	Exon 2 of 7	ENSP00000451540.1

Frequencies

GnomAD3 genomes

AF:

0.989

AC:

150566

AN:

152240

Hom.:

74466

Cov.:

show subpopulations

Gnomad AFR

AF:

0.962

Gnomad AMI

AF:

1.00

Gnomad AMR

AF:

0.997

Gnomad ASJ

AF:

1.00

Gnomad EAS

AF:

1.00

Gnomad SAS

AF:

1.00

Gnomad FIN

AF:

1.00

Gnomad MID

AF:

0.997

Gnomad NFE

AF:

1.00

Gnomad OTH

AF:

0.989

GnomAD2 exomes

AF:

0.997

AC:

250717

AN:

251402

AF XY:

0.998

show subpopulations

Gnomad AFR exome

AF:

0.963

Gnomad AMR exome

AF:

0.998

Gnomad ASJ exome

AF:

1.00

Gnomad EAS exome

AF:

1.00

Gnomad FIN exome

AF:

1.00

Gnomad NFE exome

AF:

1.00

Gnomad OTH exome

AF:

0.998

GnomAD4 exome

AF:

0.999

AC:

1460221

AN:

1461822

Hom.:

729332

Cov.:

AF XY:

0.999

AC XY:

726535

AN XY:

727214

show subpopulations

African (AFR)

AF:

0.961

AC:

32187

AN:

33480

American (AMR)

AF:

0.998

AC:

44644

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

26132

AN:

26132

East Asian (EAS)

AF:

1.00

AC:

39684

AN:

39684

South Asian (SAS)

AF:

1.00

AC:

86239

AN:

86252

European-Finnish (FIN)

AF:

1.00

AC:

53406

AN:

53406

Middle Eastern (MID)

AF:

0.997

AC:

5753

AN:

5768

European-Non Finnish (NFE)

AF:

1.00

AC:

1111941

AN:

1111982

Other (OTH)

AF:

0.997

AC:

60235

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

113

227

340

454

567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

21670

43340

65010

86680

108350

<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:

0.989

AC:

150683

AN:

152358

Hom.:

74524

Cov.:

AF XY:

0.989

AC XY:

73704

AN XY:

74506

show subpopulations

African (AFR)

AF:

0.962

AC:

39991

AN:

41582

American (AMR)

AF:

0.997

AC:

15254

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

1.00

AC:

3472

AN:

3472

East Asian (EAS)

AF:

1.00

AC:

5187

AN:

5188

South Asian (SAS)

AF:

1.00

AC:

4826

AN:

4826

European-Finnish (FIN)

AF:

1.00

AC:

10622

AN:

10622

Middle Eastern (MID)

AF:

0.997

AC:

293

AN:

294

European-Non Finnish (NFE)

AF:

1.00

AC:

68032

AN:

68040

Other (OTH)

AF:

0.990

AC:

2094

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

177

265

354

442

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

916

1832

2748

3664

4580

<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:

0.995

Hom.:

149227

Bravo

AF:

0.987

TwinsUK

AF:

1.00

AC:

3708

ALSPAC

AF:

1.00

AC:

3854

ESP6500AA

AF:

0.967

AC:

4260

ESP6500EA

AF:

1.00

AC:

8600

ExAC

AF:

0.997

AC:

121019

Asia WGS

AF:

0.999

AC:

3475

AN:

3478

EpiCase

AF:

1.00

EpiControl

AF:

1.00

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (5)

Colorectal cancer, hereditary nonpolyposis, type 7 (3)

not provided (2)

Endometrial carcinoma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.40

(source)

DANN

Benign

0.69

DEOGEN2

Benign

0.089

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.4

FATHMM_MKL

Benign

0.050

LIST_S2

Benign

0.034

MetaRNN

Benign

0.0000017

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

0.32

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.26

REVEL

Benign

0.14

Sift

Benign

0.85

Sift4G

Benign

0.85

Polyphen

0.0

Vest4

0.017

MPC

0.11

ClinPred

0.00016

GERP RS

1.3

PromoterAI

0.082

Neutral

(source)

Varity_R

0.041

gMVP

0.094

Mutation Taster

=298/2

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over