14-75022929-C-T

Variant names:

• chr14-75022929-C-T
• rs175057
• NM_001040108.2:c.4012-37G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001040108.2(MLH3):​c.4012-37G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 1,613,404 control chromosomes in the GnomAD database, including 175,840 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.46 (16571 hom., cov: 31)
  • Exomes 𝑓: 0.46 (159269 hom.)
• Consequence: MLH3 NM_001040108.2 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.0790
• Publications: 39 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
• intestinal polyposis syndrome

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 14-75022929-C-T is Benign according to our data. Variant chr14-75022929-C-T is described in ClinVar as Benign. ClinVar VariationId is 1242252.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.503 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001040108.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	NM_001040108.2	MANE Select	c.4012-37G>A		intron	N/A	NP_001035197.1	Q9UHC1-1
	MLH3	NM_014381.3		c.3940-37G>A		intron	N/A	NP_055196.2	Q9UHC1-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MLH3	ENST00000355774.7	TSL:5 MANE Select	c.4012-37G>A		intron	N/A	ENSP00000348020.2	Q9UHC1-1
	MLH3	ENST00000380968.6	TSL:1	c.3940-37G>A		intron	N/A	ENSP00000370355.3	Q9UHC1-2
	MLH3	ENST00000930871.1		c.4012-37G>A		intron	N/A	ENSP00000600930.1

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69841 AN: 151872 Hom.: 16551 Cov.: 31

Gnomad AFR AF: 0.509

Gnomad AMI AF: 0.496

Gnomad AMR AF: 0.368

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.162

Gnomad SAS AF: 0.506

Gnomad FIN AF: 0.446

Gnomad MID AF: 0.545

Gnomad NFE AF: 0.470

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.422 AC: 106019 AN: 251460 AF XY: 0.433

Gnomad AFR exome AF: 0.509

Gnomad AMR exome AF: 0.248

Gnomad ASJ exome AF: 0.488

Gnomad EAS exome AF: 0.167

Gnomad FIN exome AF: 0.456

Gnomad NFE exome AF: 0.468

Gnomad OTH exome AF: 0.449

GnomAD4 exome AF: 0.461 AC: 674408 AN: 1461412 Hom.: 159269 Cov.: 36 AF XY: 0.463 AC XY: 336952 AN XY: 727036

African (AFR) AF: 0.515 AC: 17223 AN: 33472

American (AMR) AF: 0.263 AC: 11764 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.492 AC: 12853 AN: 26134

East Asian (EAS) AF: 0.172 AC: 6817 AN: 39698

South Asian (SAS) AF: 0.501 AC: 43241 AN: 86252

European-Finnish (FIN) AF: 0.458 AC: 24470 AN: 53420

Middle Eastern (MID) AF: 0.513 AC: 2960 AN: 5766

European-Non Finnish (NFE) AF: 0.474 AC: 527268 AN: 1111570

Other (OTH) AF: 0.461 AC: 27812 AN: 60378

GnomAD4 genome AF: 0.460 AC: 69902 AN: 151992 Hom.: 16571 Cov.: 31 AF XY: 0.457 AC XY: 33955 AN XY: 74308

African (AFR) AF: 0.508 AC: 21062 AN: 41420

American (AMR) AF: 0.368 AC: 5620 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1710 AN: 3470

East Asian (EAS) AF: 0.162 AC: 837 AN: 5166

South Asian (SAS) AF: 0.506 AC: 2432 AN: 4810

European-Finnish (FIN) AF: 0.446 AC: 4714 AN: 10562

Middle Eastern (MID) AF: 0.545 AC: 159 AN: 292

European-Non Finnish (NFE) AF: 0.470 AC: 31927 AN: 67980

Other (OTH) AF: 0.471 AC: 991 AN: 2102

Alfa AF: 0.469 Hom.: 14190

Bravo AF: 0.451

Asia WGS AF: 0.394 AC: 1371 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	2.7
DANN	Benign	0.46
PhyloP100		0.079
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs175057; hg19: chr14-75489632; COSMIC: COSV53153233; COSMIC: COSV53153233;