21-42371985-C-A

Position:

• chr21-42371985-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_001256317.3(TMPRSS3):​c.*777G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0115 in 454,578 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.011 (21 hom., cov: 33)
  • Exomes 𝑓: 0.012 (42 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00700

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0113 (1716/152304) while in subpopulation NFE AF= 0.0198 (1349/68014). AF 95% confidence interval is 0.019. There are 21 homozygotes in gnomad4. There are 774 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.*777G>T		3_prime_UTR_variant	13/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.*777G>T		3_prime_UTR_variant	13/13		NP_076927.1
TMPRSS3	NM_032404.3	c.*777G>T		3_prime_UTR_variant	10/10		NP_115780.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.*777G>T		3_prime_UTR_variant	13/13		NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes AF: 0.0113 AC: 1716 AN: 152186 Hom.: 21 Cov.: 33

Gnomad AFR AF: 0.00371

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00949

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00311

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0198

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0102 AC: 1390 AN: 136796 Hom.: 15 AF XY: 0.0102 AC XY: 758 AN XY: 74268

Gnomad AFR exome AF: 0.00358

Gnomad AMR exome AF: 0.00585

Gnomad ASJ exome AF: 0.000844

Gnomad EAS exome AF: 0.000375

Gnomad SAS exome AF: 0.00174

Gnomad FIN exome AF: 0.00464

Gnomad NFE exome AF: 0.0200

Gnomad OTH exome AF: 0.0121

GnomAD4 exome AF: 0.0116 AC: 3514 AN: 302274 Hom.: 42 Cov.: 0 AF XY: 0.0111 AC XY: 1916 AN XY: 172276

Gnomad4 AFR exome AF: 0.00444

Gnomad4 AMR exome AF: 0.00565

Gnomad4 ASJ exome AF: 0.000927

Gnomad4 EAS exome AF: 0.000428

Gnomad4 SAS exome AF: 0.00189

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.0189

Gnomad4 OTH exome AF: 0.00975

GnomAD4 genome AF: 0.0113 AC: 1716 AN: 152304 Hom.: 21 Cov.: 33 AF XY: 0.0104 AC XY: 774 AN XY: 74478

Gnomad4 AFR AF: 0.00370

Gnomad4 AMR AF: 0.00948

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.00311

Gnomad4 NFE AF: 0.0198

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0151 Hom.: 10

Bravo AF: 0.0111

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.1
DANN	Benign	0.42

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: rs35447393; hg19: chr21-43792094; COSMIC: COSV52306594;