rs775508015

Positions:

• chr21-42376612-C-A
• chr21-42376612-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1 PM2

The NM_001256317.3(TMPRSS3):​c.1120G>T​(p.Val374Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03

Genes affected

TMPRSS3 (HGNC:11877): (transmembrane serine protease 3) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a serine protease domain, a transmembrane domain, an LDL receptor-like domain, and a scavenger receptor cysteine-rich domain. Serine proteases are known to be involved in a variety of biological processes, whose malfunction often leads to human diseases and disorders. This gene was identified by its association with both congenital and childhood onset autosomal recessive deafness. This gene is expressed in fetal cochlea and many other tissues, and is thought to be involved in the development and maintenance of the inner ear or the contents of the perilymph and endolymph. This gene was also identified as a tumor-associated gene that is overexpressed in ovarian tumors. Alternatively spliced transcript variants have been described. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM1: In a domain Peptidase S1 (size 232) in uniprot entity TMPS3_HUMAN there are 21 pathogenic changes around while only 1 benign (95%) in NM_001256317.3
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1120G>T	p.Val374Leu	missense_variant	11/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1123G>T	p.Val375Leu	missense_variant	11/13		NP_076927.1
TMPRSS3	NM_032404.3	c.742G>T	p.Val248Leu	missense_variant	8/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1120G>T	p.Val374Leu	missense_variant	11/13		NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Uncertain	0.037	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.33	.;T;T;.
Eigen	Benign	0.059
Eigen_PC	Benign	0.11
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.30	T;.;T;T
M_CAP	Pathogenic	0.39	D
MetaRNN	Uncertain	0.54	D;D;D;D
MetaSVM	Benign	-0.38	T
MutationAssessor	Benign	0.045	.;N;N;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.1	.;.;N;N
REVEL	Uncertain	0.38
Sift	Benign	0.049	.;.;D;D
Sift4G	Uncertain	0.014	.;.;D;D
Polyphen		0.83	P;P;P;D
Vest4		0.58, 0.58
MutPred		0.58		.;Gain of loop (P = 0.2045);Gain of loop (P = 0.2045);.;
MVP		0.75
MPC		0.48
ClinPred		0.89	D
GERP RS		4.9
Varity_R		0.40
gMVP		0.78

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: rs775508015; hg19: chr21-43796721;