rs397517370

Variant names:

• chr21-42376645-A-C
• rs397517370
• NM_001256317.3:c.1087T>G

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001256317.3(TMPRSS3):​c.1087T>G​(p.Leu363Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.658
• Publications: 0 publications found

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]

TMPRSS3 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 8

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 41 curated pathogenic missense variants (we use a threshold of 10). The gene has 12 curated benign missense variants. Trascript score misZ: 0.22926 (below the threshold of 3.09). GenCC associations: The gene is linked to hearing loss, autosomal recessive, autosomal recessive nonsyndromic hearing loss 8, nonsyndromic genetic hearing loss.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1087T>G	p.Leu363Val	missense_variant	Exon 11 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1090T>G	p.Leu364Val	missense_variant	Exon 11 of 13		NP_076927.1
TMPRSS3	NM_032404.3	c.709T>G	p.Leu237Val	missense_variant	Exon 8 of 10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1087T>G	p.Leu363Val	missense_variant	Exon 11 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 23, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Leu364Val variant in TMPRSS3 has not been reported in the literature nor pre viously identified by our laboratory. Computational analyses (biochemical amino acid properties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Leu364Val variant may impact the protein, though this information is not predict ive enough to determine pathogenicity. In summary, the clinical significance of this variant cannot be determined with certainty. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Uncertain	0.063	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	.;T;T;.
Eigen	Benign	-0.69
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Uncertain	0.87	D;.;D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Uncertain	0.61	D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Benign	0.090	.;N;N;.
PhyloP100		0.66
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.4	.;.;N;N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0030	.;.;D;D
Sift4G	Uncertain	0.0070	.;.;D;D
Polyphen		0.96	D;D;D;D
Vest4		0.67, 0.65
MutPred		0.52		.;Gain of methylation at K368 (P = 0.0633);Gain of methylation at K368 (P = 0.0633);.;
MVP		0.71
MPC		0.53
ClinPred		0.95	D
GERP RS		-3.1
Varity_R		0.35
gMVP		0.79
Mutation Taster		=76/24	polymorphism

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: rs397517370; hg19: chr21-43796754;