21-42372353-G-A

Position:

• chr21-42372353-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.*409C>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 0.0293 in 457,720 control chromosomes in the GnomAD database, including 585 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.054 (476 hom., cov: 33)
  • Exomes 𝑓: 0.017 (109 hom.)
• Consequence: TMPRSS3 NM_001256317.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 21-42372353-G-A is Benign according to our data. Variant chr21-42372353-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 340047.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.146 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.*409C>T		3_prime_UTR_variant	13/13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.*409C>T		3_prime_UTR_variant	13/13		NP_076927.1
TMPRSS3	NM_032404.3	c.*409C>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.*409C>T		3_prime_UTR_variant	13/13		NM_001256317.3	ENSP00000494414	A1

Frequencies

GnomAD3 genomes AF: 0.0543 AC: 8257 AN: 152078 Hom.: 469 Cov.: 33

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.0592

Gnomad AMR AF: 0.0243

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00622

Gnomad FIN AF: 0.0464

Gnomad MID AF: 0.0285

Gnomad NFE AF: 0.0154

Gnomad OTH AF: 0.0427

GnomAD3 exomes AF: 0.0182 AC: 2365 AN: 130124 Hom.: 62 AF XY: 0.0161 AC XY: 1142 AN XY: 71088

Gnomad AFR exome AF: 0.145

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.000247

Gnomad EAS exome AF: 0.000477

Gnomad SAS exome AF: 0.00746

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0145

Gnomad OTH exome AF: 0.0182

GnomAD4 exome AF: 0.0168 AC: 5145 AN: 305524 Hom.: 109 Cov.: 0 AF XY: 0.0147 AC XY: 2549 AN XY: 173848

Gnomad4 AFR exome AF: 0.142

Gnomad4 AMR exome AF: 0.0132

Gnomad4 ASJ exome AF: 0.000273

Gnomad4 EAS exome AF: 0.000426

Gnomad4 SAS exome AF: 0.00791

Gnomad4 FIN exome AF: 0.0381

Gnomad4 NFE exome AF: 0.0141

Gnomad4 OTH exome AF: 0.0209

GnomAD4 genome AF: 0.0544 AC: 8279 AN: 152196 Hom.: 476 Cov.: 33 AF XY: 0.0535 AC XY: 3981 AN XY: 74430

Gnomad4 AFR AF: 0.149

Gnomad4 AMR AF: 0.0243

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00623

Gnomad4 FIN AF: 0.0464

Gnomad4 NFE AF: 0.0154

Gnomad4 OTH AF: 0.0422

Alfa AF: 0.0281 Hom.: 35

Bravo AF: 0.0575

Asia WGS AF: 0.0130 AC: 46 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Likely benign, 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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

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- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.87
DANN	Benign	0.44

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: rs55954914; hg19: chr21-43792462;