chr21-42395451-C-T

Variant names:

• chr21-42395451-C-T
• rs73372256
• NM_001256317.3:c.-34G>A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_001256317.3(TMPRSS3):​c.-34G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00934 in 1,565,326 control chromosomes in the GnomAD database, including 1,119 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (585 hom., cov: 32)
  • Exomes 𝑓: 0.0052 (534 hom.)
• Consequence: TMPRSS3 NM_001256317.3 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.139

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 21-42395451-C-T is Benign according to our data. Variant chr21-42395451-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 46090.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr21-42395451-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS3	NM_001256317.3	c.-34G>A		5_prime_UTR_variant	Exon 2 of 13	ENST00000644384.2	NP_001243246.1
TMPRSS3	NM_024022.4	c.-34G>A		5_prime_UTR_variant	Exon 2 of 13		NP_076927.1
TMPRSS3	NM_032405.2	c.-34G>A		5_prime_UTR_variant	Exon 2 of 9		NP_115781.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.-34G>A		5_prime_UTR_variant	Exon 2 of 13		NM_001256317.3	ENSP00000494414.1

Frequencies

GnomAD3 genomes AF: 0.0479 AC: 7284 AN: 152098 Hom.: 585 Cov.: 32

Gnomad AFR AF: 0.165

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0213

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00124

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.000647

Gnomad OTH AF: 0.0392

GnomAD3 exomes AF: 0.0129 AC: 3216 AN: 249520 Hom.: 231 AF XY: 0.00943 AC XY: 1272 AN XY: 134888

Gnomad AFR exome AF: 0.170

Gnomad AMR exome AF: 0.00986

Gnomad ASJ exome AF: 0.000398

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.000428

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000790

Gnomad OTH exome AF: 0.00622

GnomAD4 exome AF: 0.00519 AC: 7328 AN: 1413110 Hom.: 534 Cov.: 24 AF XY: 0.00450 AC XY: 3178 AN XY: 706230

Gnomad4 AFR exome AF: 0.172

Gnomad4 AMR exome AF: 0.0110

Gnomad4 ASJ exome AF: 0.000310

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.000517

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.000397

Gnomad4 OTH exome AF: 0.0118

GnomAD4 genome AF: 0.0479 AC: 7287 AN: 152216 Hom.: 585 Cov.: 32 AF XY: 0.0463 AC XY: 3448 AN XY: 74430

Gnomad4 AFR AF: 0.164

Gnomad4 AMR AF: 0.0212

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000647

Gnomad4 OTH AF: 0.0388

Alfa AF: 0.0282 Hom.: 46

Bravo AF: 0.0544

Asia WGS AF: 0.0110 AC: 39 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 13, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not specified Benign:1

Jun 28, 2011

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 8 Benign:1

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	14
DANN	Benign	0.65

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs73372256; hg19: chr21-43815560;