21-42383199-CTA-C

Position:

• chr21-42383199-CTA-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Strong PM2

The NM_001256317.3(TMPRSS3):​c.617-3_617-2del variant causes a splice acceptor, splice polypyrimidine tract, intron change. The variant was absent in control chromosomes in GnomAD project. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: TMPRSS3 NM_001256317.3 splice_acceptor, splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.11

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 Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.121145375 fraction of the gene. Cryptic splice site detected, with MaxEntScore 6.2, offset of 0 (no position change), new splice context is: aagcctttgttcccctccAGcct. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• 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.617-3_617-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.617-3_617-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_076927.1
TMPRSS3	NM_032404.3	c.236-3_236-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_115780.1
TMPRSS3	NM_032405.2	c.617-3_617-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NP_115781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.617-3_617-2del		splice_acceptor_variant, splice_polypyrimidine_tract_variant, intron_variant			NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes Cov.: 31

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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: chr21-43803308;