rs456298

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr21-41464824-T-A
• chr21-41464824-T-C
• chr21-41464824-T-G

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.*1318A>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.*1318A>T		3_prime_UTR_variant	Exon 14 of 14		NP_001128571.1
TMPRSS2	NM_001382720.1	c.*1296A>T		3_prime_UTR_variant	Exon 14 of 14		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149	c.*1318A>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_005656.4	ENSP00000330330.5

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

Gnomad4 AFR exome AF: 0.641

Gnomad4 AMR exome AF: 0.620

Gnomad4 ASJ exome AF: 0.900

Gnomad4 EAS exome AF: 0.417

Gnomad4 SAS exome AF: 0.682

Gnomad4 FIN exome AF: 0.833

Gnomad4 NFE exome AF: 0.853

Gnomad4 OTH exome AF: 0.796

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

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.670

Gnomad4 ASJ AF: 0.911

Gnomad4 EAS AF: 0.383

Gnomad4 SAS AF: 0.706

Gnomad4 FIN AF: 0.731

Gnomad4 NFE AF: 0.840

Gnomad4 OTH AF: 0.774

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.4
DANN	Benign	0.81

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: rs456298; hg19: chr21-42836751;