rs779651509

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS1

The NM_001040108.2(MLH3):c.3568C>A(p.Gln1190Lys) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000178 in 1,348,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000036 ( 0 hom., cov: 26)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

MLH3
NM_001040108.2 missense, splice_region

Scores

Splicing: ADA: 0.006586

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 4.10

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.12205157).

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.0000362 (5/138056) while in subpopulation SAS AF = 0.000682 (3/4402). AF 95% confidence interval is 0.000186. There are 0 homozygotes in GnomAd4. There are 4 alleles in the male GnomAd4 subpopulation. Median coverage is 26. This position passed quality control check.

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.3568C>A	p.Gln1190Lys	missense splice_region	Exon 5 of 13	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.3568C>A	p.Gln1190Lys	missense splice_region	Exon 5 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.3568C>A	p.Gln1190Lys	missense splice_region	Exon 5 of 13	ENSP00000348020.2	Q9UHC1-1
MLH3	ENST00000380968.6	TSL:1	c.3568C>A	p.Gln1190Lys	missense splice_region	Exon 5 of 12	ENSP00000370355.3	Q9UHC1-2
MLH3	ENST00000930871.1		c.3568C>A	p.Gln1190Lys	missense splice_region	Exon 5 of 13	ENSP00000600930.1

Frequencies

GnomAD3 genomes

AF:

0.0000362

AC:

AN:

138056

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000268

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000237

Gnomad SAS

AF:

0.000682

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000161

AC:

AN:

248514

AF XY:

0.0000223

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1210874

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

612354

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

27506

American (AMR)

AF:

0.00

AC:

AN:

41712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22930

East Asian (EAS)

AF:

0.00

AC:

AN:

29576

South Asian (SAS)

AF:

0.000210

AC:

AN:

81094

European-Finnish (FIN)

AF:

0.00

AC:

AN:

47370

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5154

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

905590

Other (OTH)

AF:

0.0000400

AC:

AN:

49942

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.549

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000362

AC:

AN:

138056

Hom.:

Cov.:

AF XY:

0.0000606

AC XY:

AN XY:

66030

show subpopulations

African (AFR)

AF:

0.0000268

AC:

AN:

37346

American (AMR)

AF:

0.00

AC:

AN:

12446

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3418

East Asian (EAS)

AF:

0.000237

AC:

AN:

4212

South Asian (SAS)

AF:

0.000682

AC:

AN:

4402

European-Finnish (FIN)

AF:

0.00

AC:

AN:

7880

Middle Eastern (MID)

AF:

0.00

AC:

AN:

268

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

65358

Other (OTH)

AF:

0.00

AC:

AN:

1846

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.635

Heterozygous variant carriers

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:

0.00

Hom.:

ExAC

AF:

0.0000165

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (2)

Colorectal cancer, hereditary nonpolyposis, type 7 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.30

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.086

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.052

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.79

M_CAP

Benign

0.014

MetaRNN

Benign

0.12

MetaSVM

Benign

-0.72

MutationAssessor

Benign

0.13

PhyloP100

4.1

PrimateAI

Benign

0.43

PROVEAN

Benign

-0.40

REVEL

Benign

0.17

Sift

Benign

0.49

Sift4G

Benign

0.52

Polyphen

0.019

Vest4

0.18

MutPred

0.52

Gain of catalytic residue at I1186 (P = 0.002)

MVP

0.81

MPC

0.18

ClinPred

0.15

GERP RS

4.9

Varity_R

0.077

gMVP

0.37

Mutation Taster

=64/36

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0066

dbscSNV1_RF

Benign

0.14

SpliceAI score (max)

0.020

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over