rs12329760

Positions:

chr21-41480570-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts U:1B:2

Conservation

PhyloP100: 1.49

Variant links:

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]

TMPRSS2 links:

TMPRSS2 (HGNC:):

TMPRSS2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 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_multiple_submitters_no_conflicts, 2 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	Protein	UniProt
TMPRSS2	NM_005656.4 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/14	ENST00000332149.10	NP_005647.3	O15393-1
TMPRSS2	NM_001135099.1 linkuse as main transcript	c.589G>A	p.Val197Met	missense_variant	6/14		NP_001128571.1	O15393-2
TMPRSS2	NM_001382720.1 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/14		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10 linkuse as main transcript	c.478G>A	p.Val160Met	missense_variant	6/14	1	NM_005656.4	ENSP00000330330.5		O15393-1

Frequencies

GnomAD3 genomes

AF:

0.252

AC:

38327

AN:

152004

Hom.:

5298

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.234

AC XY:

170309

AN XY:

726950

show subpopulations

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.:

AF XY:

0.259

AC XY:

19230

AN XY:

74384

show subpopulations

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:1Benign:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 26, 2021	This variant is associated with the following publications: (PMID: 32867305) -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.25

CADD

Uncertain

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

LIST_S2

Benign

0.74

.;T;T;T;T

MetaRNN

Benign

0.0018

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Pathogenic

3.3

M;.;M;.;.

PrimateAI

Benign

0.47

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

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over