rs3761373

Variant names:

• chr21-41498595-C-T
• rs3761373
• NM_005656.4:c.-56-406G>A

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 6 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 -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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005656.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS2	NM_005656.4	MANE Select	c.-56-406G>A		intron	N/A	NP_005647.3
	TMPRSS2	NM_001135099.1		c.56-406G>A		intron	N/A	NP_001128571.1
	TMPRSS2	NM_001382720.1		c.-56-406G>A		intron	N/A	NP_001369649.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS2	ENST00000332149.10	TSL:1 MANE Select	c.-56-406G>A		intron	N/A	ENSP00000330330.5
	TMPRSS2	ENST00000454499.6	TSL:1	c.-56-406G>A		intron	N/A	ENSP00000389006.2
	TMPRSS2	ENST00000679263.1		c.104-406G>A		intron	N/A	ENSP00000504602.1

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

African (AFR) AF: 0.0976 AC: 4055 AN: 41548

American (AMR) AF: 0.0860 AC: 1316 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.111 AC: 386 AN: 3470

East Asian (EAS) AF: 0.289 AC: 1494 AN: 5174

South Asian (SAS) AF: 0.175 AC: 843 AN: 4812

European-Finnish (FIN) AF: 0.0980 AC: 1039 AN: 10602

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.0846 AC: 5755 AN: 67998

Other (OTH) AF: 0.121 AC: 255 AN: 2114

Alfa AF: 0.0903 Hom.: 1075

Bravo AF: 0.0973

Asia WGS AF: 0.192 AC: 667 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	4.4
DANN	Benign	0.43
PhyloP100		0.33
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: rs3761373; hg19: chr21-42870522;