14-75017109-T-C

Position:

chr14-75017109-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001040108.2(MLH3):c.4335A>G(p.Gln1445Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.536 in 1,612,868 control chromosomes in the GnomAD database, including 236,314 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.53 ( 21708 hom., cov: 33)

Exomes 𝑓: 0.54 ( 214606 hom. )

Consequence

MLH3
NM_001040108.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: -0.637

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 links:

MLH3 (HGNC:):

MLH3 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 14-75017109-T-C is Benign according to our data. Variant chr14-75017109-T-C is described in ClinVar as [Benign]. Clinvar id is 257253.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-75017109-T-C is described in Lovd as [Benign]. Variant chr14-75017109-T-C is described in Lovd as [Likely_pathogenic].

BP7

Synonymous conserved (PhyloP=-0.637 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.816 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2 linkuse as main transcript	c.4335A>G	p.Gln1445Gln	synonymous_variant	13/13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 linkuse as main transcript	c.4335A>G	p.Gln1445Gln	synonymous_variant	13/13	5	NM_001040108.2	ENSP00000348020.2		Q9UHC1-1

Frequencies

GnomAD3 genomes

AF:

0.526

AC:

79996

AN:

152034

Hom.:

21692

Cov.:

show subpopulations

Gnomad AFR

AF:

0.442

Gnomad AMI

AF:

0.508

Gnomad AMR

AF:

0.627

Gnomad ASJ

AF:

0.510

Gnomad EAS

AF:

0.836

Gnomad SAS

AF:

0.495

Gnomad FIN

AF:

0.554

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.530

Gnomad OTH

AF:

0.523

GnomAD3 exomes

AF:

0.575

AC:

144593

AN:

251482

Hom.:

43389

AF XY:

0.564

AC XY:

76668

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.443

Gnomad AMR exome

AF:

0.749

Gnomad ASJ exome

AF:

0.515

Gnomad EAS exome

AF:

0.833

Gnomad SAS exome

AF:

0.498

Gnomad FIN exome

AF:

0.545

Gnomad NFE exome

AF:

0.532

Gnomad OTH exome

AF:

0.549

GnomAD4 exome

AF:

0.537

AC:

784611

AN:

1460716

Hom.:

214606

Cov.:

AF XY:

0.535

AC XY:

389080

AN XY:

726696

show subpopulations

Gnomad4 AFR exome

AF:

0.433

Gnomad4 AMR exome

AF:

0.734

Gnomad4 ASJ exome

AF:

0.511

Gnomad4 EAS exome

AF:

0.828

Gnomad4 SAS exome

AF:

0.498

Gnomad4 FIN exome

AF:

0.542

Gnomad4 NFE exome

AF:

0.526

Gnomad4 OTH exome

AF:

0.536

GnomAD4 genome

AF:

0.526

AC:

80052

AN:

152152

Hom.:

21708

Cov.:

AF XY:

0.529

AC XY:

39380

AN XY:

74386

show subpopulations

Gnomad4 AFR

AF:

0.443

Gnomad4 AMR

AF:

0.627

Gnomad4 ASJ

AF:

0.510

Gnomad4 EAS

AF:

0.837

Gnomad4 SAS

AF:

0.495

Gnomad4 FIN

AF:

0.554

Gnomad4 NFE

AF:

0.530

Gnomad4 OTH

AF:

0.516

Alfa

AF:

0.530

Hom.:

26377

Bravo

AF:

0.532

Asia WGS

AF:

0.603

AC:

2099

AN:

3478

EpiCase

AF:

0.532

EpiControl

AF:

0.535

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:5

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 30, 2020	This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:3

Benign, criteria provided, single submitter	clinical testing	KCCC/NGS Laboratory, Kuwait Cancer Control Center	Jul 07, 2023	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 22, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

2.2

DANN

Benign

0.59

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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