14-75042443-G-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001040108.2(MLH3):c.3315C>A(p.Asp1105Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00332 in 1,614,088 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D1105N) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0030 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0033 ( 10 hom. )

Consequence

MLH3
NM_001040108.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 0.714

Publications

15 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
intestinal polyposis syndrome
Inheritance: AR Classification: LIMITED Submitted by: ClinGen

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=0.005310178).

BP6

Variant 14-75042443-G-T is Benign according to our data. Variant chr14-75042443-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 416452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00302 (460/152260) while in subpopulation NFE AF = 0.00397 (270/68018). AF 95% confidence interval is 0.00358. There are 2 homozygotes in GnomAd4. There are 243 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 2 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.3315C>A	p.Asp1105Glu	missense	Exon 3 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.3315C>A	p.Asp1105Glu	missense	Exon 3 of 12	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MLH3	ENST00000355774.7	TSL:5 MANE Select	c.3315C>A	p.Asp1105Glu	missense	Exon 3 of 13	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6	TSL:1	c.3315C>A	p.Asp1105Glu	missense	Exon 3 of 12	ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000930871.1		c.3315C>A	p.Asp1105Glu	missense	Exon 3 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes

AF:

0.00302

AC:

460

AN:

152142

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000555

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000982

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.0131

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00397

Gnomad OTH

AF:

0.00191

GnomAD2 exomes

AF:

0.00315

AC:

793

AN:

251490

AF XY:

0.00312

show subpopulations

Gnomad AFR exome

AF:

0.000554

Gnomad AMR exome

AF:

0.00121

Gnomad ASJ exome

AF:

0.00129

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.00376

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00335

AC:

4895

AN:

1461828

Hom.:

Cov.:

AF XY:

0.00336

AC XY:

2442

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.000388

AC:

AN:

33480

American (AMR)

AF:

0.00101

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000995

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00124

AC:

107

AN:

86258

European-Finnish (FIN)

AF:

0.0110

AC:

590

AN:

53412

Middle Eastern (MID)

AF:

0.00208

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00354

AC:

3939

AN:

1111962

Other (OTH)

AF:

0.00270

AC:

163

AN:

60392

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

259

517

776

1034

1293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.00302

AC:

460

AN:

152260

Hom.:

Cov.:

AF XY:

0.00326

AC XY:

243

AN XY:

74436

show subpopulations

African (AFR)

AF:

0.000554

AC:

AN:

41542

American (AMR)

AF:

0.000980

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.000415

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.0131

AC:

139

AN:

10614

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00397

AC:

270

AN:

68018

Other (OTH)

AF:

0.00189

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.487

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00327

Hom.:

Bravo

AF:

0.00210

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00337

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.00290

AC:

352

EpiCase

AF:

0.00349

EpiControl

AF:

0.00284

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Colorectal cancer, hereditary nonpolyposis, type 7 (3)

Colorectal cancer;C0476089:Endometrial carcinoma;C1858380:Colorectal cancer, hereditary nonpolyposis, type 7 (1)

Endometrial carcinoma (1)

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.32

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.36

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0053

MetaSVM

Benign

-0.97

MutationAssessor

Benign

1.6

PhyloP100

0.71

PrimateAI

Benign

0.36

PROVEAN

Benign

-0.41

REVEL

Benign

0.036

Sift

Benign

0.46

Sift4G

Benign

0.42

Polyphen

0.060

Vest4

0.099

MutPred

0.34

Gain of catalytic residue at L1108 (P = 0.0045)

MVP

0.79

MPC

0.12

ClinPred

0.0092

GERP RS

1.6

Varity_R

0.022

gMVP

0.19

Mutation Taster

=95/5

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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

Computational scores

Splicing

Publications

Other links and lift over