dbSNP rs12329760: TMPRSS2:p.Val160Leu (chr21-41480570-C-A) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_005656.4(TMPRSS2):c.478G>T(p.Val160Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,432 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V160M) has been classified as Benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TMPRSS2
NM_005656.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.49

Publications

0 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
TMPRSS2	NM_005656.4 link	c.478G>T	p.Val160Leu	missense_variant	Exon 6 of 14	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1 link	c.589G>T	p.Val197Leu	missense_variant	Exon 6 of 14		NP_001128571.1
TMPRSS2	NM_001382720.1 link	c.478G>T	p.Val160Leu	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 link	c.478G>T	p.Val160Leu	missense_variant	Exon 6 of 14	1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461432

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727002

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53022

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111972

Other (OTH)

AF:

0.00

AC:

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.020

BayesDel_noAF

Benign

-0.27

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.13

T;.;T;.;T

Eigen

Uncertain

0.41

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.89

.;D;D;D;D

M_CAP

Benign

0.083

MetaRNN

Uncertain

0.51

D;D;D;D;D

MetaSVM

Uncertain

-0.028

MutationAssessor

Pathogenic

3.3

M;.;M;.;.

PhyloP100

1.5

PrimateAI

Benign

0.46

PROVEAN

Benign

-1.9

N;N;N;N;N

REVEL

Benign

0.26

Sift

Uncertain

0.028

D;D;D;D;D

Sift4G

Uncertain

0.028

D;D;D;D;.

Polyphen

0.87

P;.;P;.;.

Vest4

0.39

MutPred

0.39

Loss of MoRF binding (P = 0.1828);.;Loss of MoRF binding (P = 0.1828);Loss of MoRF binding (P = 0.1828);.;

MVP

0.86

MPC

0.44

ClinPred

0.94

GERP RS

4.2

Varity_R

0.36

gMVP

0.61

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over