21-41486440-T-C

Variant names:

• chr21-41486440-T-C
• rs383510
• NM_005656.4:c.445+1954A>G

Variant summary

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

The NM_005656.4(TMPRSS2):​c.445+1954A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.571 in 151,984 control chromosomes in the GnomAD database, including 25,173 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 0.57 (25156 hom., cov: 31)
  • Exomes 𝑓: 0.56 (17 hom.)
• Consequence: TMPRSS2 NM_005656.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.634

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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.445+1954A>G		intron_variant	Intron 5 of 13	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.556+1954A>G		intron_variant	Intron 5 of 13		NP_001128571.1
TMPRSS2	NM_001382720.1	c.445+1954A>G		intron_variant	Intron 5 of 13		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.445+1954A>G		intron_variant	Intron 5 of 13	1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes AF: 0.571 AC: 86599 AN: 151756 Hom.: 25105 Cov.: 31

Gnomad AFR AF: 0.647

Gnomad AMI AF: 0.454

Gnomad AMR AF: 0.587

Gnomad ASJ AF: 0.484

Gnomad EAS AF: 0.660

Gnomad SAS AF: 0.565

Gnomad FIN AF: 0.641

Gnomad MID AF: 0.564

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.576

GnomAD4 exome AF: 0.565 AC: 61 AN: 108 Hom.: 17 Cov.: 0 AF XY: 0.550 AC XY: 44 AN XY: 80

Gnomad4 AFR exome AF: 1.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.750

Gnomad4 NFE exome AF: 0.563

Gnomad4 OTH exome AF: 1.00

GnomAD4 genome AF: 0.571 AC: 86714 AN: 151876 Hom.: 25156 Cov.: 31 AF XY: 0.579 AC XY: 42965 AN XY: 74218

Gnomad4 AFR AF: 0.648

Gnomad4 AMR AF: 0.587

Gnomad4 ASJ AF: 0.484

Gnomad4 EAS AF: 0.660

Gnomad4 SAS AF: 0.564

Gnomad4 FIN AF: 0.641

Gnomad4 NFE AF: 0.509

Gnomad4 OTH AF: 0.575

Alfa AF: 0.546 Hom.: 2849

Bravo AF: 0.572

Asia WGS AF: 0.650 AC: 2261 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	2.6
DANN	Benign	0.48

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: rs383510; hg19: chr21-42858367;