14-75013942-G-A

Variant names:

• chr14-75013942-G-A
• rs77514025
• NM_001040108.2:c.*3140C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001040108.2(MLH3):​c.*3140C>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 0.00841 in 190,892 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0099 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (0 hom.)
• Consequence: MLH3 NM_001040108.2 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:3
• Conservation: PhyloP100: -0.796
• Publications: 0 publications found

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

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 14-75013942-G-A is Benign according to our data. Variant chr14-75013942-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 314346.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00986 (1501/152286) while in subpopulation AFR AF = 0.0332 (1378/41548). AF 95% confidence interval is 0.0317. There are 30 homozygotes in GnomAd4. There are 711 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.*3140C>T		3_prime_UTR_variant	Exon 13 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.*3140C>T		3_prime_UTR_variant	Exon 13 of 13	5	NM_001040108.2	ENSP00000348020.2
MLH3	ENST00000380968.6	c.*3140C>T		3_prime_UTR_variant	Exon 12 of 12	1		ENSP00000370355.3

Frequencies

GnomAD3 genomes AF: 0.00986 AC: 1501 AN: 152168 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0333

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00281

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0100

GnomAD4 exome AF: 0.00272 AC: 105 AN: 38606 Hom.: 0 Cov.: 0 AF XY: 0.00262 AC XY: 47 AN XY: 17946

African (AFR) AF: 0.0357 AC: 56 AN: 1568

American (AMR) AF: 0.00 AC: 0 AN: 978

Ashkenazi Jewish (ASJ) AF: 0.0138 AC: 34 AN: 2462

East Asian (EAS) AF: 0.00 AC: 0 AN: 6854

South Asian (SAS) AF: 0.00 AC: 0 AN: 332

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 20

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 248

European-Non Finnish (NFE) AF: 0.0000870 AC: 2 AN: 22980

Other (OTH) AF: 0.00411 AC: 13 AN: 3164

GnomAD4 genome AF: 0.00986 AC: 1501 AN: 152286 Hom.: 30 Cov.: 32 AF XY: 0.00955 AC XY: 711 AN XY: 74460

African (AFR) AF: 0.0332 AC: 1378 AN: 41548

American (AMR) AF: 0.00281 AC: 43 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.0130 AC: 45 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68024

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00484 Hom.: 2

Bravo AF: 0.0115

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, single submitter

Submissions by phenotype

Colorectal cancer, hereditary nonpolyposis, type 7 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Likely 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely 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: Likely 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	-0.88
CADD	Benign	0.19
DANN	Benign	0.78
PhyloP100		-0.80
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs77514025; hg19: chr14-75480645;