chr21-41473479-T-C

Variant names:

• chr21-41473479-T-C
• rs1473161161
• NM_005656.4:c.745A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005656.4(TMPRSS2):​c.745A>G​(p.Asn249Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,456,544 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: TMPRSS2 NM_005656.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.00
• Publications: 2 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10125229).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TMPRSS2	NM_005656.4	c.745A>G	p.Asn249Asp	missense_variant	Exon 9 of 14	ENST00000332149.10	NP_005647.3
TMPRSS2	NM_001135099.1	c.856A>G	p.Asn286Asp	missense_variant	Exon 9 of 14		NP_001128571.1
TMPRSS2	NM_001382720.1	c.745A>G	p.Asn249Asp	missense_variant	Exon 9 of 14		NP_001369649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TMPRSS2	ENST00000332149.10	c.745A>G	p.Asn249Asp	missense_variant	Exon 9 of 14	1	NM_005656.4	ENSP00000330330.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1456544 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 724124

African (AFR) AF: 0.0000598 AC: 2 AN: 33418

American (AMR) AF: 0.00 AC: 0 AN: 44386

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25998

East Asian (EAS) AF: 0.00 AC: 0 AN: 39572

South Asian (SAS) AF: 0.00 AC: 0 AN: 85614

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5520

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110046

Other (OTH) AF: 0.00 AC: 0 AN: 60172

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.856A>G (p.N286D) alteration is located in exon 9 (coding exon 9) of the TMPRSS2 gene. This alteration results from a A to G substitution at nucleotide position 856, causing the asparagine (N) at amino acid position 286 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.080	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	5.7
DANN	Benign	0.73
DEOGEN2	Benign	0.11	T;.;T;.;T
Eigen	Benign	-0.99
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.035	N
LIST_S2	Benign	0.54	.;T;T;T;T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.10	T;T;T;T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.27	N;.;N;.;.
PhyloP100		0.0
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.4	N;N;N;N;N
REVEL	Benign	0.18
Sift	Benign	0.41	T;T;T;T;T
Sift4G	Benign	0.57	T;T;T;T;.
Polyphen		0.24	B;.;B;.;.
Vest4		0.14
MutPred		0.38		Loss of MoRF binding (P = 0.0569);.;Loss of MoRF binding (P = 0.0569);Loss of MoRF binding (P = 0.0569);.;
MVP		0.61
MPC		0.15
ClinPred		0.14	T
GERP RS		2.2
Varity_R		0.17
gMVP		0.39
Mutation Taster		=92/8	polymorphism

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: rs1473161161; hg19: chr21-42845406;