rs12329760

Positions:

• chr21-41480570-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005656.4(TMPRSS2):​c.478G>A​(p.Val160Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.236 in 1,613,468 control chromosomes in the GnomAD database, including 47,374 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.25 (5307 hom., cov: 33)
  • Exomes 𝑓: 0.23 (42067 hom.)
• Consequence: TMPRSS2 NM_005656.4 missense
• Clinical Significance: Benign criteria provided, single submitter U:1 B:1
• Conservation: PhyloP100: 1.49

Genes affected

TMPRSS2 (HGNC:11876): (transmembrane serine protease 2) This gene encodes a protein that belongs to the serine protease family. The encoded protein contains a type II transmembrane domain, a receptor class A domain, a scavenger receptor cysteine-rich domain and a protease domain. Serine proteases are known to be involved in many physiological and pathological processes. This gene was demonstrated to be up-regulated by androgenic hormones in prostate cancer cells and down-regulated in androgen-independent prostate cancer tissue. The protease domain of this protein is thought to be cleaved and secreted into cell media after autocleavage. This protein also facilitates entry of viruses into host cells by proteolytically cleaving and activating viral envelope glycoproteins. Viruses found to use this protein for cell entry include Influenza virus and the human coronaviruses HCoV-229E, MERS-CoV, SARS-CoV and SARS-CoV-2 (COVID-19 virus). Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Apr 2020]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.001753658).
• BP6: Variant 21-41480570-C-T is Benign according to our data. Variant chr21-41480570-C-T is described in ClinVar as [Benign]. Clinvar id is 1257425.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.373 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TMPRSS2	NM_005656.4	c.478G>A	p.Val160Met	missense_variant	6/14	ENST00000332149.10
TMPRSS2	NM_001135099.1	c.589G>A	p.Val197Met	missense_variant	6/14
TMPRSS2	NM_001382720.1	c.478G>A	p.Val160Met	missense_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.478G>A	p.Val160Met	missense_variant	6/14	1	NM_005656.4	P1

Frequencies

GnomAD3 genomes AF: 0.252 AC: 38327 AN: 152004 Hom.: 5298 Cov.: 33

Gnomad AFR AF: 0.288

Gnomad AMI AF: 0.258

Gnomad AMR AF: 0.157

Gnomad ASJ AF: 0.138

Gnomad EAS AF: 0.387

Gnomad SAS AF: 0.239

Gnomad FIN AF: 0.394

Gnomad MID AF: 0.177

Gnomad NFE AF: 0.228

Gnomad OTH AF: 0.204

GnomAD3 exomes AF: 0.245 AC: 61407 AN: 250738 Hom.: 8263 AF XY: 0.244 AC XY: 33153 AN XY: 135764

Gnomad AFR exome AF: 0.294

Gnomad AMR exome AF: 0.153

Gnomad ASJ exome AF: 0.136

Gnomad EAS exome AF: 0.381

Gnomad SAS exome AF: 0.248

Gnomad FIN exome AF: 0.371

Gnomad NFE exome AF: 0.230

Gnomad OTH exome AF: 0.224

GnomAD4 exome AF: 0.234 AC: 342061 AN: 1461346 Hom.: 42067 Cov.: 39 AF XY: 0.234 AC XY: 170309 AN XY: 726950

Gnomad4 AFR exome AF: 0.293

Gnomad4 AMR exome AF: 0.153

Gnomad4 ASJ exome AF: 0.133

Gnomad4 EAS exome AF: 0.382

Gnomad4 SAS exome AF: 0.244

Gnomad4 FIN exome AF: 0.364

Gnomad4 NFE exome AF: 0.226

Gnomad4 OTH exome AF: 0.227

GnomAD4 genome AF: 0.252 AC: 38372 AN: 152122 Hom.: 5307 Cov.: 33 AF XY: 0.259 AC XY: 19230 AN XY: 74384

Gnomad4 AFR AF: 0.289

Gnomad4 AMR AF: 0.157

Gnomad4 ASJ AF: 0.138

Gnomad4 EAS AF: 0.388

Gnomad4 SAS AF: 0.238

Gnomad4 FIN AF: 0.394

Gnomad4 NFE AF: 0.228

Gnomad4 OTH AF: 0.206

Alfa AF: 0.226 Hom.: 8325

Bravo AF: 0.237

TwinsUK AF: 0.215 AC: 799

ALSPAC AF: 0.218 AC: 840

ESP6500AA AF: 0.290 AC: 1279

ESP6500EA AF: 0.216 AC: 1860

ExAC AF: 0.249 AC: 30280

Asia WGS AF: 0.320 AC: 1116 AN: 3478

EpiCase AF: 0.213

EpiControl AF: 0.203

ClinVar

Significance: Benign

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Associated with severe COVID-19 disease Uncertain:1

Uncertain significance, no assertion criteria provided

research

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Jul 01, 2023

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 26, 2021

This variant is associated with the following publications: (PMID: 32867305) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.32
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.25
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.30	T;.;T;.;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.54
FATHMM_MKL	Uncertain	0.76	D
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M;.;M;.;.
MutationTaster	Benign	0.077	P;P;P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	-1.9	N;N;N;N;N
REVEL	Benign	0.28
Sift	Uncertain	0.019	D;D;D;D;T
Sift4G	Uncertain	0.0090	D;D;D;D;.
Polyphen		1.0	D;.;D;.;.
Vest4		0.20
MPC		0.58
ClinPred		0.059	T
GERP RS		4.2
Varity_R		0.26
gMVP		0.60

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: rs12329760; hg19: chr21-42852497; COSMIC: COSV59820912;