21-41480570-C-T

Variant names:

• chr21-41480570-C-T
• rs12329760
• NM_005656.4:c.478G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong 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. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• 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, multiple submitters, no conflicts U:1 B:2
• Conservation: PhyloP100: 1.49
• Publications: 240 publications found

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

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 14	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.589G>A	p.Val197Met	missense_variant	Exon 6 of 14		NP_001128571.1
TMPRSS2	NM_001382720.1	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 14		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.478G>A	p.Val160Met	missense_variant	Exon 6 of 14	1	NM_005656.4	ENSP00000330330.5

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

GnomAD2 exomes AF: 0.245 AC: 61407 AN: 250738 AF XY: 0.244

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 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

African (AFR) AF: 0.293 AC: 9803 AN: 33476

American (AMR) AF: 0.153 AC: 6850 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.133 AC: 3488 AN: 26136

East Asian (EAS) AF: 0.382 AC: 15164 AN: 39696

South Asian (SAS) AF: 0.244 AC: 21065 AN: 86246

European-Finnish (FIN) AF: 0.364 AC: 19268 AN: 53006

Middle Eastern (MID) AF: 0.195 AC: 1124 AN: 5768

European-Non Finnish (NFE) AF: 0.226 AC: 251562 AN: 1111916

Other (OTH) AF: 0.227 AC: 13737 AN: 60388

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

African (AFR) AF: 0.289 AC: 11969 AN: 41482

American (AMR) AF: 0.157 AC: 2401 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.138 AC: 478 AN: 3470

East Asian (EAS) AF: 0.388 AC: 2002 AN: 5166

South Asian (SAS) AF: 0.238 AC: 1147 AN: 4826

European-Finnish (FIN) AF: 0.394 AC: 4169 AN: 10592

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.228 AC: 15484 AN: 67974

Other (OTH) AF: 0.206 AC: 435 AN: 2114

Alfa AF: 0.232 Hom.: 17308

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Feb 26, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

Associated with severe COVID-19 disease Uncertain:1

Jul 01, 2023

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: research

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
LIST_S2	Benign	0.0	.;T;T;T;T
MetaRNN	Benign	0.0018	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.3	M;.;M;.;.
PhyloP100		1.5
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;.
Vest4		0.20
ClinPred		0.059	T
GERP RS		4.2
Varity_R		0.26
gMVP		0.60
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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