chr21-42389012-C-T

Position:

• chr21-42389012-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM2 PM5 BP4_Strong BS1_Supporting

The NM_001256317.3(TMPRSS3):​c.239G>A​(p.Arg80His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000186 in 1,614,124 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R80C) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00018 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00019 (1 hom.)
• Consequence: TMPRSS3 NM_001256317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2 B:1
• Conservation: PhyloP100: 2.03

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr21-42389013-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 228296.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Uncertain_significance=1}.
• BP4: Computational evidence support a benign effect (MetaRNN=0.01501891).
• BS1: Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.000187 (274/1461848) while in subpopulation EAS AF= 0.0035 (139/39700). AF 95% confidence interval is 0.00303. There are 1 homozygotes in gnomad4_exome. There are 155 alleles in male gnomad4_exome subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS3	NM_001256317.3	c.239G>A	p.Arg80His	missense_variant	4/13	ENST00000644384.2
TMPRSS3	NM_024022.4	c.239G>A	p.Arg80His	missense_variant	4/13
TMPRSS3	NM_032405.2	c.239G>A	p.Arg80His	missense_variant	4/9
TMPRSS3	NM_032404.3	c.-143G>A		5_prime_UTR_variant	1/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS3	ENST00000644384.2	c.239G>A	p.Arg80His	missense_variant	4/13		NM_001256317.3	A1

Frequencies

GnomAD3 genomes AF: 0.000177 AC: 27 AN: 152158 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00270

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000326 AC: 82 AN: 251358 Hom.: 0 AF XY: 0.000346 AC XY: 47 AN XY: 135866

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00437

Gnomad EAS exome AF: 0.00158

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000528

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000187 AC: 274 AN: 1461848 Hom.: 1 Cov.: 32 AF XY: 0.000213 AC XY: 155 AN XY: 727224

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.00310

Gnomad4 EAS exome AF: 0.00350

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.000348

GnomAD4 genome AF: 0.000177 AC: 27 AN: 152276 Hom.: 0 Cov.: 33 AF XY: 0.000215 AC XY: 16 AN XY: 74458

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000948

Alfa AF: 0.000299 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000321 AC: 39

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Aug 16, 2022	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 80 of the TMPRSS3 protein (p.Arg80His). This variant is present in population databases (rs146159479, gnomAD 0.4%). This missense change has been observed in individual(s) with non syndromic deafness (PMID: 26346818, 32235586). ClinVar contains an entry for this variant (Variation ID: 179855). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt TMPRSS3 protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 01, 2023	Observed as a heterozygous variant with no second TMPRSS3 variant identified in a patient with hearing loss in the published literature (Wong et al., 2020); Published functional studies demonstrate a damaging effect due to reduced proteolytic activity (Wong et al., 2020); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 34426522, 26346818, 32235586, 34868270) -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 16, 2014

p.Arg80His in exon 4 of TMPRSS3: This variant is not expected to have clinical s ignificance due to a lack of conservation across species, including mammals. Of note, 5 mammals (mouse, rat, golden hamster, chinese hamster, and prairie vole) have a histidine (His) at this position despite high nearby amino acid conservat ion. In addition, computational prediction tools do not suggest a high likelihoo d of impact to the protein. This variant has been identified in 0.12% (11/8650) of East Asian chromosomes by the Exome Aggregation Consortium (ExAC, http://exac .broadinstitute.org; dbSNP rs146159479). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.090
CADD	Benign	19
DANN	Benign	0.96
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.22
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.84	T;.;T;T;T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.015	T;T;T;T;T
MetaSVM	Uncertain	-0.16	T
MutationAssessor	Benign	1.5	L;L;L;.;L
MutationTaster	Benign	0.98	N;N;N;N;N
PrimateAI	Benign	0.28	T
Polyphen		0.0070	B;B;B;.;B
Vest4		0.44, 0.43, 0.43, 0.47
MVP		0.96
MPC		0.15
ClinPred		0.024	T
GERP RS		4.3
Varity_R		0.043
gMVP		0.69

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: rs146159479; hg19: chr21-43809121; COSMIC: COSV99368015;