chr21-41470061-G-A

Variant names:

• chr21-41470061-G-A
• rs2070788
• NM_005656.4:c.1171+587C>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.1171+587C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.586 in 152,008 control chromosomes in the GnomAD database, including 26,653 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 0.59 (26653 hom., cov: 32)
• Consequence: TMPRSS2 NM_005656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.619
• Publications: 102 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]

MX1 (HGNC:7532): (MX dynamin like GTPase 1) This gene encodes a guanosine triphosphate (GTP)-metabolizing protein that participates in the cellular antiviral response. The encoded protein is induced by type I and type II interferons and antagonizes the replication process of several different RNA and DNA viruses. There is a related gene located adjacent to this gene on chromosome 21, and there are multiple pseudogenes located in a cluster on chromosome 4. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Sep 2013]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.69 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.1171+587C>T		intron_variant	Intron 11 of 13	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.1282+587C>T		intron_variant	Intron 11 of 13		NP_001128571.1
TMPRSS2	NM_001382720.1	c.1171+587C>T		intron_variant	Intron 11 of 13		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.1171+587C>T		intron_variant	Intron 11 of 13	1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes AF: 0.586 AC: 89007 AN: 151886 Hom.: 26620 Cov.: 32

Gnomad AFR AF: 0.696

Gnomad AMI AF: 0.543

Gnomad AMR AF: 0.496

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.652

Gnomad SAS AF: 0.556

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.533

Gnomad OTH AF: 0.567

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

GnomAD4 genome AF: 0.586 AC: 89096 AN: 152008 Hom.: 26653 Cov.: 32 AF XY: 0.590 AC XY: 43801 AN XY: 74274

African (AFR) AF: 0.697 AC: 28878 AN: 41446

American (AMR) AF: 0.496 AC: 7570 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1759 AN: 3464

East Asian (EAS) AF: 0.652 AC: 3369 AN: 5166

South Asian (SAS) AF: 0.556 AC: 2679 AN: 4816

European-Finnish (FIN) AF: 0.641 AC: 6767 AN: 10564

Middle Eastern (MID) AF: 0.568 AC: 167 AN: 294

European-Non Finnish (NFE) AF: 0.533 AC: 36222 AN: 67966

Other (OTH) AF: 0.564 AC: 1191 AN: 2110

Alfa AF: 0.554 Hom.: 91299

Bravo AF: 0.584

Asia WGS AF: 0.639 AC: 2223 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.47
PhyloP100		-0.62
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: rs2070788; hg19: chr21-42841988;