chr21-41482276-A-G

Variant names:

• chr21-41482276-A-G
• rs2276205
• NM_005656.4:c.446-1674T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001135099.1(TMPRSS2):​c.557-1674T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.102 in 152,064 control chromosomes in the GnomAD database, including 933 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 0.10 (933 hom., cov: 32)
• Consequence: TMPRSS2 NM_001135099.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0630
• Publications: 6 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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.0).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.188 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001135099.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS2	NM_005656.4	MANE Select	c.446-1674T>C		intron	N/A	NP_005647.3
	TMPRSS2	NM_001135099.1		c.557-1674T>C		intron	N/A	NP_001128571.1
	TMPRSS2	NM_001382720.1		c.446-1674T>C		intron	N/A	NP_001369649.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS2	ENST00000332149.10	TSL:1 MANE Select	c.446-1674T>C		intron	N/A	ENSP00000330330.5
	TMPRSS2	ENST00000454499.6	TSL:1	c.446-1674T>C		intron	N/A	ENSP00000389006.2
	TMPRSS2	ENST00000679263.1		c.605-1674T>C		intron	N/A	ENSP00000504602.1

Frequencies

GnomAD3 genomes AF: 0.101 AC: 15418 AN: 151946 Hom.: 932 Cov.: 32

Gnomad AFR AF: 0.124

Gnomad AMI AF: 0.0680

Gnomad AMR AF: 0.0616

Gnomad ASJ AF: 0.0433

Gnomad EAS AF: 0.197

Gnomad SAS AF: 0.0622

Gnomad FIN AF: 0.177

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0846

Gnomad OTH AF: 0.0919

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

GnomAD4 genome AF: 0.102 AC: 15443 AN: 152064 Hom.: 933 Cov.: 32 AF XY: 0.105 AC XY: 7826 AN XY: 74352

African (AFR) AF: 0.124 AC: 5141 AN: 41466

American (AMR) AF: 0.0615 AC: 941 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0433 AC: 150 AN: 3466

East Asian (EAS) AF: 0.198 AC: 1020 AN: 5148

South Asian (SAS) AF: 0.0621 AC: 299 AN: 4816

European-Finnish (FIN) AF: 0.177 AC: 1877 AN: 10578

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.0846 AC: 5749 AN: 67982

Other (OTH) AF: 0.0914 AC: 193 AN: 2112

Alfa AF: 0.0826 Hom.: 923

Bravo AF: 0.0954

Asia WGS AF: 0.108 AC: 376 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.42
DANN	Benign	0.31
PhyloP100		-0.063
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: rs2276205; hg19: chr21-42854203; COSMIC: COSV59820921;