rs3761373

Positions:

• chr21-41498595-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005656.4(TMPRSS2):​c.-56-406G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.1 in 152,228 control chromosomes in the GnomAD database, including 943 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.10 (943 hom., cov: 32)
• Consequence: TMPRSS2 NM_005656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.331

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.277 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.-56-406G>A		intron_variant		ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.56-406G>A		intron_variant			NP_001128571.1
TMPRSS2	NM_001382720.1	c.-56-406G>A		intron_variant			NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.-56-406G>A		intron_variant		1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes AF: 0.100 AC: 15213 AN: 152110 Hom.: 944 Cov.: 32

Gnomad AFR AF: 0.0975

Gnomad AMI AF: 0.0396

Gnomad AMR AF: 0.0861

Gnomad ASJ AF: 0.111

Gnomad EAS AF: 0.289

Gnomad SAS AF: 0.174

Gnomad FIN AF: 0.0980

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0847

Gnomad OTH AF: 0.122

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.100 AC: 15220 AN: 152228 Hom.: 943 Cov.: 32 AF XY: 0.102 AC XY: 7581 AN XY: 74432

Gnomad4 AFR AF: 0.0976

Gnomad4 AMR AF: 0.0860

Gnomad4 ASJ AF: 0.111

Gnomad4 EAS AF: 0.289

Gnomad4 SAS AF: 0.175

Gnomad4 FIN AF: 0.0980

Gnomad4 NFE AF: 0.0846

Gnomad4 OTH AF: 0.121

Alfa AF: 0.0911 Hom.: 849

Bravo AF: 0.0973

Asia WGS AF: 0.192 AC: 667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.43

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: rs3761373; hg19: chr21-42870522; COSMIC: COSV59820941;