14-75013934-T-C

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.*3148A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 194,262 control chromosomes in the GnomAD database, including 17,816 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14021 hom., cov: 32)

Exomes 𝑓: 0.41 ( 3795 hom. )

Consequence

MLH3
NM_001040108.2 3_prime_UTR

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: -2.97

Publications

29 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 (BayesDel_noAF=-0.94).

BP6

Variant 14-75013934-T-C is Benign according to our data. Variant chr14-75013934-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 314345.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.454 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2 link	c.*3148A>G		3_prime_UTR_variant	Exon 13 of 13	ENST00000355774.7	NP_001035197.1	Q9UHC1-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7 link	c.*3148A>G		3_prime_UTR_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2		Q9UHC1-1
MLH3	ENST00000380968.6 link	c.*3148A>G		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000370355.3		Q9UHC1-2

Frequencies

GnomAD3 genomes

AF:

0.423

AC:

64288

AN:

151936

Hom.:

14006

Cov.:

show subpopulations

Gnomad AFR

AF:

0.406

Gnomad AMI

AF:

0.473

Gnomad AMR

AF:

0.353

Gnomad ASJ

AF:

0.485

Gnomad EAS

AF:

0.155

Gnomad SAS

AF:

0.461

Gnomad FIN

AF:

0.446

Gnomad MID

AF:

0.519

Gnomad NFE

AF:

0.459

Gnomad OTH

AF:

0.437

GnomAD4 exome

AF:

0.412

AC:

17383

AN:

42208

Hom.:

3795

Cov.:

AF XY:

0.412

AC XY:

8028

AN XY:

19492

show subpopulations

African (AFR)

AF:

0.433

AC:

764

AN:

1764

American (AMR)

AF:

0.353

AC:

393

AN:

1114

Ashkenazi Jewish (ASJ)

AF:

0.488

AC:

1304

AN:

2672

East Asian (EAS)

AF:

0.168

AC:

1197

AN:

7132

South Asian (SAS)

AF:

0.492

AC:

184

AN:

374

European-Finnish (FIN)

AF:

0.600

AC:

AN:

Middle Eastern (MID)

AF:

0.500

AC:

136

AN:

272

European-Non Finnish (NFE)

AF:

0.467

AC:

11859

AN:

25408

Other (OTH)

AF:

0.444

AC:

1534

AN:

3452

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

461

922

1383

1844

2305

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.423

AC:

64338

AN:

152054

Hom.:

14021

Cov.:

AF XY:

0.421

AC XY:

31324

AN XY:

74336

show subpopulations

African (AFR)

AF:

0.406

AC:

16843

AN:

41472

American (AMR)

AF:

0.352

AC:

5384

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.485

AC:

1683

AN:

3470

East Asian (EAS)

AF:

0.155

AC:

800

AN:

5174

South Asian (SAS)

AF:

0.461

AC:

2218

AN:

4814

European-Finnish (FIN)

AF:

0.446

AC:

4719

AN:

10572

Middle Eastern (MID)

AF:

0.517

AC:

151

AN:

292

European-Non Finnish (NFE)

AF:

0.459

AC:

31174

AN:

67954

Other (OTH)

AF:

0.444

AC:

936

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1867

3734

5600

7467

9334

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.449

Hom.:

2585

Bravo

AF:

0.411

Asia WGS

AF:

0.364

AC:

1265

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Feb 18, 2020

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is associated with the following publications: (PMID: 29516665) -

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Colorectal cancer, hereditary nonpolyposis, type 7

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Lynch syndrome

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Vanishing white matter disease

Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.94

CADD

Benign

0.032

(source)

DANN

Benign

0.28

PhyloP100

-3.0

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

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14-75013934-T-C

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over