NM_005656.4:c.445+1954A>G

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 57 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=-1.01).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.642 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.445+1954A>G		intron	N/A	NP_005647.3
	TMPRSS2	NM_001135099.1		c.556+1954A>G		intron	N/A	NP_001128571.1	O15393-2
	TMPRSS2	NM_001382720.1		c.445+1954A>G		intron	N/A	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.445+1954A>G		intron	N/A	ENSP00000330330.5	O15393-1
	TMPRSS2	ENST00000454499.6	TSL:1	c.445+1954A>G		intron	N/A	ENSP00000389006.2	O15393-1
	TMPRSS2	ENST00000679263.1		c.604+1954A>G		intron	N/A	ENSP00000504602.1	A0A7I2V650

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

African (AFR) AF: 1.00 AC: 2 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.750 AC: 3 AN: 4

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2

European-Non Finnish (NFE) AF: 0.563 AC: 54 AN: 96

Other (OTH) AF: 1.00 AC: 2 AN: 2

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

African (AFR) AF: 0.648 AC: 26816 AN: 41390

American (AMR) AF: 0.587 AC: 8972 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.484 AC: 1680 AN: 3468

East Asian (EAS) AF: 0.660 AC: 3401 AN: 5150

South Asian (SAS) AF: 0.564 AC: 2707 AN: 4802

European-Finnish (FIN) AF: 0.641 AC: 6763 AN: 10556

Middle Eastern (MID) AF: 0.586 AC: 171 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34579 AN: 67926

Other (OTH) AF: 0.575 AC: 1214 AN: 2112

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	2.6
DANN	Benign	0.48
PhyloP100		-0.63
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: rs383510; hg19: chr21-42858367;