21-41464824-T-A

Variant names:

• chr21-41464824-T-A
• rs456298
• NM_005656.4:c.*1318A>T

Variant summary

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

The NM_005656.4(TMPRSS2):​c.*1318A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.751 in 233,154 control chromosomes in the GnomAD database, including 68,033 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 0.74 (42894 hom., cov: 33)
  • Exomes 𝑓: 0.77 (25139 hom.)
• Consequence: TMPRSS2 NM_005656.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 17 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]

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

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.834 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005656.4. 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.*1318A>T		3_prime_UTR	Exon 14 of 14	NP_005647.3
	TMPRSS2	NM_001135099.1		c.*1318A>T		3_prime_UTR	Exon 14 of 14	NP_001128571.1	O15393-2
	TMPRSS2	NM_001382720.1		c.*1296A>T		3_prime_UTR	Exon 14 of 14	NP_001369649.1	A0A7I2V474

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TMPRSS2	ENST00000332149.10	TSL:1 MANE Select	c.*1318A>T		3_prime_UTR	Exon 14 of 14	ENSP00000330330.5	O15393-1
	TMPRSS2	ENST00000679263.1		c.*1318A>T		3_prime_UTR	Exon 14 of 14	ENSP00000504602.1	A0A7I2V650
	TMPRSS2	ENST00000864264.1		c.*1318A>T		3_prime_UTR	Exon 15 of 15	ENSP00000534323.1

Frequencies

GnomAD3 genomes AF: 0.740 AC: 112597 AN: 152064 Hom.: 42888 Cov.: 33

Gnomad AFR AF: 0.635

Gnomad AMI AF: 0.843

Gnomad AMR AF: 0.671

Gnomad ASJ AF: 0.911

Gnomad EAS AF: 0.383

Gnomad SAS AF: 0.704

Gnomad FIN AF: 0.731

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.840

Gnomad OTH AF: 0.778

GnomAD4 exome AF: 0.771 AC: 62431 AN: 80972 Hom.: 25139 Cov.: 0 AF XY: 0.778 AC XY: 28962 AN XY: 37210

African (AFR) AF: 0.641 AC: 2495 AN: 3894

American (AMR) AF: 0.620 AC: 1548 AN: 2496

Ashkenazi Jewish (ASJ) AF: 0.900 AC: 4610 AN: 5124

East Asian (EAS) AF: 0.417 AC: 4756 AN: 11402

South Asian (SAS) AF: 0.682 AC: 479 AN: 702

European-Finnish (FIN) AF: 0.833 AC: 50 AN: 60

Middle Eastern (MID) AF: 0.864 AC: 425 AN: 492

European-Non Finnish (NFE) AF: 0.853 AC: 42678 AN: 50028

Other (OTH) AF: 0.796 AC: 5390 AN: 6774

GnomAD4 genome AF: 0.740 AC: 112634 AN: 152182 Hom.: 42894 Cov.: 33 AF XY: 0.730 AC XY: 54282 AN XY: 74402

African (AFR) AF: 0.634 AC: 26306 AN: 41488

American (AMR) AF: 0.670 AC: 10252 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.911 AC: 3164 AN: 3472

East Asian (EAS) AF: 0.383 AC: 1975 AN: 5160

South Asian (SAS) AF: 0.706 AC: 3407 AN: 4826

European-Finnish (FIN) AF: 0.731 AC: 7754 AN: 10602

Middle Eastern (MID) AF: 0.878 AC: 258 AN: 294

European-Non Finnish (NFE) AF: 0.840 AC: 57113 AN: 68022

Other (OTH) AF: 0.774 AC: 1636 AN: 2114

Alfa AF: 0.772 Hom.: 5710

Bravo AF: 0.732

Asia WGS AF: 0.529 AC: 1841 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.81
PhyloP100		-0.062
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: rs456298; hg19: chr21-42836751;