rs727504304

Positions:

• chr21-42376543-G-A

Variant summary

Our verdict is Pathogenic. Variant got 13 ACMG points: 13P and 0B. PVS1 PM2 PP3 PP5_Moderate

The NM_001256317.3(TMPRSS3):​c.1189C>T​(p.Gln397Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: TMPRSS3 NM_001256317.3 stop_gained, splice_region
• Scores: Splicing: ADA: 0.9942
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.98

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 Pathogenic. Variant got 13 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.
• PP5: Variant 21-42376543-G-A is Pathogenic according to our data. Variant chr21-42376543-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 177740.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-42376543-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.1189C>T	p.Gln397Ter	stop_gained, splice_region_variant	11/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.1192C>T	p.Gln398Ter	stop_gained, splice_region_variant	11/13		NP_076927.1
TMPRSS3	NM_032404.3	c.811C>T	p.Gln271Ter	stop_gained, splice_region_variant	8/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.1189C>T	p.Gln397Ter	stop_gained, splice_region_variant	11/13		NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 15, 2013

The Gln398X variant in TMPRSS3 has been previously reported in 1 homozygous indi vidual with SNHL, was found to segregate with disease in 2 affected homozygous r elatives, and has not been identified in large population studies. This nonsense variant leads to a premature termination codon at position 398, which is predic ted to lead to a truncated or absent protein. In summary, this variant meets our criteria to be classified as pathogenic (http://pcpgm.partners.org/LMM). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.62
CADD	Pathogenic	54
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.93
FATHMM_MKL	Benign	0.24	N
MutationTaster	Benign	1.0	A;A;A;A
Vest4		0.91, 0.84
GERP RS		4.9

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.010		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: rs727504304; hg19: chr21-43796652; COSMIC: COSV105105562;