14-75047221-C-T

Position:

• chr14-75047221-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_001040108.2(MLH3):​c.2435G>A​(p.Ser812Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MLH3 NM_001040108.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -1.10

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 Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.044674993).
• BP6: Variant 14-75047221-C-T is Benign according to our data. Variant chr14-75047221-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1791214.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MLH3	NM_001040108.2	c.2435G>A	p.Ser812Asn	missense_variant	2/13	ENST00000355774.7	NP_001035197.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MLH3	ENST00000355774.7	c.2435G>A	p.Ser812Asn	missense_variant	2/13	5	NM_001040108.2	ENSP00000348020	P1
MLH3	ENST00000380968.6	c.2435G>A	p.Ser812Asn	missense_variant	2/12	1		ENSP00000370355
MLH3	ENST00000556257.5	c.2435G>A	p.Ser812Asn	missense_variant	2/7	5		ENSP00000451540
MLH3	ENST00000555671.1			upstream_gene_variant		5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 30, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	0.0020
DANN	Benign	0.20
DEOGEN2	Benign	0.11	T;.;.;T
Eigen	Benign	-2.0
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.18	T;T;T;.
M_CAP	Benign	0.049	D
MetaRNN	Benign	0.045	T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-0.28	N;N;.;N
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-0.67	N;.;N;N
REVEL	Benign	0.17
Sift	Benign	0.74	T;.;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.012
MutPred		0.26		Gain of catalytic residue at E810 (P = 0.0135);Gain of catalytic residue at E810 (P = 0.0135);Gain of catalytic residue at E810 (P = 0.0135);Gain of catalytic residue at E810 (P = 0.0135);
MVP		0.46
MPC		0.092
ClinPred		0.015	T
GERP RS		-9.6
Varity_R		0.031
gMVP		0.082

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: chr14-75513924;