17-3897828-T-C

Position:

• chr17-3897828-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000225538.4(P2RX1):​c.1186A>G​(p.Met396Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00115 in 1,613,272 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0065 (9 hom., cov: 30)
  • Exomes 𝑓: 0.00060 (8 hom.)
• Consequence: P2RX1 ENST00000225538.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.38

Genes affected

P2RX1 (HGNC:8533): (purinergic receptor P2X 1) The protein encoded by this gene belongs to the P2X family of G-protein-coupled receptors. These proteins can form homo-and heterotimers and function as ATP-gated ion channels and mediate rapid and selective permeability to cations. This protein is primarily localized to smooth muscle where binds ATP and mediates synaptic transmission between neurons and from neurons to smooth muscle and may being responsible for sympathetic vasoconstriction in small arteries, arterioles and vas deferens. Mouse studies suggest that this receptor is essential for normal male reproductive function. This protein may also be involved in promoting apoptosis. [provided by RefSeq, Jun 2013]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030928552).
• BP6: Variant 17-3897828-T-C is Benign according to our data. Variant chr17-3897828-T-C is described in ClinVar as [Benign]. Clinvar id is 786300.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00647 (985/152202) while in subpopulation AFR AF= 0.0222 (920/41530). AF 95% confidence interval is 0.021. There are 9 homozygotes in gnomad4. There are 467 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
P2RX1	NM_002558.4	c.1186A>G	p.Met396Val	missense_variant	12/12	ENST00000225538.4	NP_002549.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
P2RX1	ENST00000225538.4	c.1186A>G	p.Met396Val	missense_variant	12/12	1	NM_002558.4	ENSP00000225538	P1
P2RX1	ENST00000572418.1	n.1709A>G		non_coding_transcript_exon_variant	11/11	2

Frequencies

GnomAD3 genomes AF: 0.00646 AC: 982 AN: 152084 Hom.: 9 Cov.: 30

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00574

GnomAD3 exomes AF: 0.00171 AC: 430 AN: 250744 Hom.: 5 AF XY: 0.00128 AC XY: 173 AN XY: 135602

Gnomad AFR exome AF: 0.0227

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000618

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000595 AC: 870 AN: 1461070 Hom.: 8 Cov.: 32 AF XY: 0.000513 AC XY: 373 AN XY: 726848

Gnomad4 AFR exome AF: 0.0204

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000464

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.00138

GnomAD4 genome AF: 0.00647 AC: 985 AN: 152202 Hom.: 9 Cov.: 30 AF XY: 0.00627 AC XY: 467 AN XY: 74428

Gnomad4 AFR AF: 0.0222

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00568

Alfa AF: 0.00110 Hom.: 2

Bravo AF: 0.00709

ESP6500AA AF: 0.0218 AC: 96

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.00192 AC: 233

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000178

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 30, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	13
DANN	Benign	0.73
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.72	D
LIST_S2	Benign	0.60	T
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.76	N
MutationTaster	Benign	0.83	N
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.36	N
REVEL	Benign	0.073
Sift	Benign	0.088	T
Sift4G	Benign	0.36	T
Polyphen		0.0010	B
Vest4		0.28
MVP		0.15
MPC		0.34
ClinPred		0.0038	T
GERP RS		0.92
Varity_R		0.055
gMVP		0.72

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs34617528; hg19: chr17-3801122; COSMIC: COSV50123448; COSMIC: COSV50123448;