14-75013934-T-C

Position:

• chr14-75013934-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -2.97

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]

ACMG classification

Verdict is Benign. Variant got -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/exons	MANE	UniProt
MLH3	NM_001040108.2	c.*3148A>G		3_prime_UTR_variant	13/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.*3148A>G		3_prime_UTR_variant	13/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.*3148A>G		3_prime_UTR_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64288 AN: 151936 Hom.: 14006 Cov.: 32

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.: 0 AF XY: 0.412 AC XY: 8028 AN XY: 19492

Gnomad4 AFR exome AF: 0.433

Gnomad4 AMR exome AF: 0.353

Gnomad4 ASJ exome AF: 0.488

Gnomad4 EAS exome AF: 0.168

Gnomad4 SAS exome AF: 0.492

Gnomad4 FIN exome AF: 0.600

Gnomad4 NFE exome AF: 0.467

Gnomad4 OTH exome AF: 0.444

GnomAD4 genome AF: 0.423 AC: 64338 AN: 152054 Hom.: 14021 Cov.: 32 AF XY: 0.421 AC XY: 31324 AN XY: 74336

Gnomad4 AFR AF: 0.406

Gnomad4 AMR AF: 0.352

Gnomad4 ASJ AF: 0.485

Gnomad4 EAS AF: 0.155

Gnomad4 SAS AF: 0.461

Gnomad4 FIN AF: 0.446

Gnomad4 NFE AF: 0.459

Gnomad4 OTH AF: 0.444

Alfa AF: 0.448 Hom.: 2501

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

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 18, 2020	This variant is associated with the following publications: (PMID: 29516665) -

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

Lynch syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Vanishing white matter disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.032
DANN	Benign	0.28

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

Other links and lift over

dbSNP: rs108621; hg19: chr14-75480637;