Genetic Variant NM_005656.4:c.445+1954A>G (chr21-41486440-T-C) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

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

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.634

Publications

57 publications found

Variant links:

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]

TMPRSS2 links:

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ACMG classification

Classification was made for transcript

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.

Transcripts

RefSeq

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

show subpopulations

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:

AN:

108

Hom.:

Cov.:

AF XY:

0.550

AC XY:

AN XY:

show subpopulations

African (AFR)

AF:

1.00

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AF:

0.00

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.750

AC:

AN:

Middle Eastern (MID)

AF:

0.00

AC:

AN:

European-Non Finnish (NFE)

AF:

0.563

AC:

AN:

Other (OTH)

AF:

1.00

AC:

AN:

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.571

AC:

86714

AN:

151876

Hom.:

25156

Cov.:

AF XY:

0.579

AC XY:

42965

AN XY:

74218

show subpopulations

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

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

1894

3788

5683

7577

9471

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

740

1480

2220

2960

3700

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

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

(source)

DANN

Benign

0.48

PhyloP100

-0.63

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over