rs760072474

Variant names:

• chr14-75049615-C-G
• NM_001040108.2:c.41G>C

Your query was ambiguous. Multiple possible variants found:

• chr14-75049615-C-G
• chr14-75049615-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001040108.2(MLH3):​c.41G>C​(p.Arg14Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.90

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.89

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.41G>C	p.Arg14Pro	missense_variant	Exon 2 of 13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.41G>C	p.Arg14Pro	missense_variant	Exon 2 of 13	5	NM_001040108.2	ENSP00000348020.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 23, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.R14P variant (also known as c.41G>C), located in coding exon 1 of the MLH3 gene, results from a G to C substitution at nucleotide position 41. The arginine at codon 14 is replaced by proline, an amino acid with dissimilar properties. This amino acid position is conserved. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.91
BayesDel_addAF	Pathogenic	0.50	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.69	D;.;.;D;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	D;D;D;.;D;D
M_CAP	Uncertain	0.21	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D
MetaSVM	Pathogenic	0.94	D
MutationAssessor	Pathogenic	3.4	M;M;.;M;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Pathogenic	-6.1	D;.;D;D;D;D
REVEL	Pathogenic	0.89
Sift	Uncertain	0.0020	D;.;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;.;.
Polyphen		1.0	D;D;.;D;.;.
Vest4		0.92
MutPred		0.62		Gain of catalytic residue at L17 (P = 0.0014);Gain of catalytic residue at L17 (P = 0.0014);Gain of catalytic residue at L17 (P = 0.0014);Gain of catalytic residue at L17 (P = 0.0014);Gain of catalytic residue at L17 (P = 0.0014);Gain of catalytic residue at L17 (P = 0.0014);
MVP		0.99
MPC		0.62
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.95
gMVP		0.85

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr14-75516318;