chr14-75014117-G-A

Position:

• chr14-75014117-G-A

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.*2965C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0254 in 176,456 control chromosomes in the GnomAD database, including 233 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.029 (230 hom., cov: 32)
  • Exomes 𝑓: 0.0041 (3 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.0460

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=-0.87).
• BP6: Variant 14-75014117-G-A is Benign according to our data. Variant chr14-75014117-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314349.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0977 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MLH3	NM_001040108.2	c.*2965C>T		3_prime_UTR_variant	13/13	ENST00000355774.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MLH3	ENST00000355774.7	c.*2965C>T		3_prime_UTR_variant	13/13	5	NM_001040108.2	P1
MLH3	ENST00000380968.6	c.*2965C>T		3_prime_UTR_variant	12/12	1

Frequencies

GnomAD3 genomes AF: 0.0288 AC: 4378 AN: 152170 Hom.: 230 Cov.: 32

Gnomad AFR AF: 0.100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0102

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000191

Gnomad OTH AF: 0.0206

GnomAD4 exome AF: 0.00414 AC: 100 AN: 24168 Hom.: 3 Cov.: 0 AF XY: 0.00301 AC XY: 34 AN XY: 11278

Gnomad4 AFR exome AF: 0.0995

Gnomad4 AMR exome AF: 0.00940

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000204

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000142

Gnomad4 OTH exome AF: 0.00829

GnomAD4 genome AF: 0.0288 AC: 4383 AN: 152288 Hom.: 230 Cov.: 32 AF XY: 0.0277 AC XY: 2062 AN XY: 74472

Gnomad4 AFR AF: 0.100

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000830

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000191

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0357 Hom.: 31

Bravo AF: 0.0333

Asia WGS AF: 0.00318 AC: 11 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

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. -

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

Likely 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	-0.87
CADD	Benign	1.7
DANN	Benign	0.53

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: rs10134636; hg19: chr14-75480820;