21-42371947-T-C

Position:

• chr21-42371947-T-C

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001256317.3(TMPRSS3):​c.*815A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0084 in 454,588 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0078 (13 hom., cov: 33)
  • Exomes 𝑓: 0.0087 (24 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: -0.179

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 21-42371947-T-C is Benign according to our data. Variant chr21-42371947-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 340040.We mark this variant Likely_benign, oryginal submissions are: {Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00781 (1189/152264) while in subpopulation NFE AF= 0.0119 (811/68018). AF 95% confidence interval is 0.0112. There are 13 homozygotes in gnomad4. There are 565 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.*815A>G		3_prime_UTR_variant	13/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.*815A>G		3_prime_UTR_variant	13/13		NP_076927.1
TMPRSS3	NM_032404.3	c.*815A>G		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.*815A>G		3_prime_UTR_variant	13/13		NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes AF: 0.00782 AC: 1190 AN: 152146 Hom.: 13 Cov.: 33

Gnomad AFR AF: 0.00181

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00995

Gnomad ASJ AF: 0.0239

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0119

Gnomad OTH AF: 0.00764

GnomAD3 exomes AF: 0.00815 AC: 1116 AN: 136970 Hom.: 11 AF XY: 0.00810 AC XY: 602 AN XY: 74316

Gnomad AFR exome AF: 0.00264

Gnomad AMR exome AF: 0.00454

Gnomad ASJ exome AF: 0.0226

Gnomad EAS exome AF: 0.000187

Gnomad SAS exome AF: 0.00409

Gnomad FIN exome AF: 0.00204

Gnomad NFE exome AF: 0.0118

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.00870 AC: 2631 AN: 302324 Hom.: 24 Cov.: 0 AF XY: 0.00833 AC XY: 1436 AN XY: 172304

Gnomad4 AFR exome AF: 0.00304

Gnomad4 AMR exome AF: 0.00473

Gnomad4 ASJ exome AF: 0.0228

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00396

Gnomad4 FIN exome AF: 0.00180

Gnomad4 NFE exome AF: 0.0116

Gnomad4 OTH exome AF: 0.00804

GnomAD4 genome AF: 0.00781 AC: 1189 AN: 152264 Hom.: 13 Cov.: 33 AF XY: 0.00759 AC XY: 565 AN XY: 74460

Gnomad4 AFR AF: 0.00181

Gnomad4 AMR AF: 0.00993

Gnomad4 ASJ AF: 0.0239

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00477

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.0119

Gnomad4 OTH AF: 0.00756

Alfa AF: 0.0126 Hom.: 5

Bravo AF: 0.00753

Asia WGS AF: 0.00289 AC: 10 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Apr 01, 2023

TMPRSS3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	0.49
DANN	Benign	0.80

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: rs116974943; hg19: chr21-43792056;