21-41493397-G-A

Variant names:

• chr21-41493397-G-A
• rs7275220
• NM_005656.4:c.238+959C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005656.4(TMPRSS2):​c.238+959C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.659 in 151,632 control chromosomes in the GnomAD database, including 34,363 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 0.66 (34363 hom., cov: 29)
• Consequence: TMPRSS2 NM_005656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.154

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=-1.0).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.748 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.238+959C>T		intron_variant	Intron 3 of 13	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.349+959C>T		intron_variant	Intron 3 of 13		NP_001128571.1
TMPRSS2	NM_001382720.1	c.238+959C>T		intron_variant	Intron 3 of 13		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.238+959C>T		intron_variant	Intron 3 of 13	1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes AF: 0.659 AC: 99844 AN: 151514 Hom.: 34365 Cov.: 29

Gnomad AFR AF: 0.558

Gnomad AMI AF: 0.767

Gnomad AMR AF: 0.523

Gnomad ASJ AF: 0.676

Gnomad EAS AF: 0.257

Gnomad SAS AF: 0.663

Gnomad FIN AF: 0.827

Gnomad MID AF: 0.671

Gnomad NFE AF: 0.753

Gnomad OTH AF: 0.639

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

GnomAD4 genome AF: 0.659 AC: 99876 AN: 151632 Hom.: 34363 Cov.: 29 AF XY: 0.656 AC XY: 48574 AN XY: 74032

African (AFR) AF: 0.557 AC: 23017 AN: 41296

American (AMR) AF: 0.522 AC: 7955 AN: 15238

Ashkenazi Jewish (ASJ) AF: 0.676 AC: 2343 AN: 3466

East Asian (EAS) AF: 0.257 AC: 1314 AN: 5116

South Asian (SAS) AF: 0.664 AC: 3177 AN: 4786

European-Finnish (FIN) AF: 0.827 AC: 8683 AN: 10502

Middle Eastern (MID) AF: 0.660 AC: 194 AN: 294

European-Non Finnish (NFE) AF: 0.753 AC: 51153 AN: 67918

Other (OTH) AF: 0.638 AC: 1344 AN: 2108

Alfa AF: 0.696 Hom.: 25967

Bravo AF: 0.629

Asia WGS AF: 0.449 AC: 1566 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.25
DANN	Benign	0.30
PhyloP100		-0.15
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

Publications

LitVar

Other links and lift over

dbSNP: rs7275220; hg19: chr21-42865324;