rs8134378

Positions:

• chr21-41521831-G-A
• chr21-41521831-G-T

Variant summary

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

The ENST00000454499.6(TMPRSS2):​c.-57+8142C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 152,152 control chromosomes in the GnomAD database, including 1,208 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 (1208 hom., cov: 32)
• Consequence: TMPRSS2 ENST00000454499.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.890

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]

(HGNC:):

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
		n.41521831G>A		intergenic_region

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000454499.6	c.-57+8142C>T		intron_variant		1		ENSP00000389006.2

Frequencies

GnomAD3 genomes AF: 0.115 AC: 17536 AN: 152034 Hom.: 1208 Cov.: 32

Gnomad AFR AF: 0.180

Gnomad AMI AF: 0.113

Gnomad AMR AF: 0.0626

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0791

Gnomad FIN AF: 0.110

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: 0.115 AC: 17545 AN: 152152 Hom.: 1208 Cov.: 32 AF XY: 0.114 AC XY: 8443 AN XY: 74382

Gnomad4 AFR AF: 0.179

Gnomad4 AMR AF: 0.0625

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0796

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.100

Gnomad4 OTH AF: 0.112

Alfa AF: 0.0767 Hom.: 192

Bravo AF: 0.115

Asia WGS AF: 0.0350 AC: 122 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.36
DANN	Benign	0.48

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs8134378; hg19: chr21-42893758;