rs6517673

chr21-41520129-G-A

Variant summary

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

The ENST00000454499.6(TMPRSS2):c.-57+9844C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,182 control chromosomes in the GnomAD database, including 1,213 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 0.12 (1213 hom., cov: 32)
• Consequence: TMPRSS2 ENST00000454499.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.48

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

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.177 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TMPRSS2	ENST00000454499.6	c.-57+9844C>T		intron_variant		1		P1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17612 AN: 152064 Hom.: 1213 Cov.: 32

Gnomad AFR AF: 0.181

Gnomad AMI AF: 0.112

Gnomad AMR AF: 0.0635

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0796

Gnomad FIN AF: 0.109

Gnomad MID AF: 0.171

Gnomad NFE AF: 0.100

Gnomad OTH AF: 0.114

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

GnomAD4 genome AF: 0.116 AC: 17621 AN: 152182 Hom.: 1213 Cov.: 32 AF XY: 0.114 AC XY: 8490 AN XY: 74398

Gnomad4 AFR AF: 0.181

Gnomad4 AMR AF: 0.0634

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0801

Gnomad4 FIN AF: 0.109

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.112

Alfa AF: 0.103 Hom.: 1173

Bravo AF: 0.116

Asia WGS AF: 0.0340 AC: 121 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
Cadd	Benign	0.37
Dann	Benign	0.70

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs6517673; hg19: chr21-42892056;