rs2070788

chr21-41470061-G-A

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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/exons	MANE	UniProt
TMPRSS2	NM_005656.4	c.1171+587C>T		intron_variant		ENST00000332149.10
TMPRSS2	NM_001135099.1	c.1282+587C>T		intron_variant
TMPRSS2	NM_001382720.1	c.1171+587C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.1171+587C>T		intron_variant		1	NM_005656.4	P1

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

Gnomad4 AFR AF: 0.697

Gnomad4 AMR AF: 0.496

Gnomad4 ASJ AF: 0.508

Gnomad4 EAS AF: 0.652

Gnomad4 SAS AF: 0.556

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.533

Gnomad4 OTH AF: 0.564

Alfa AF: 0.544 Hom.: 36928

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

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: rs2070788; hg19: chr21-42841988;