17-3679768-A-C

Variant names:

• chr17-3679768-A-C
• rs2050187455
• NM_002561.4:c.1081T>G

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_002561.4(P2RX5):​c.1081T>G​(p.Ser361Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: P2RX5 NM_002561.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.377

Genes affected

P2RX5 (HGNC:8536): (purinergic receptor P2X 5) The product of this gene belongs to the family of purinoceptors for ATP. This receptor functions as a ligand-gated ion channel. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the neighboring downstream gene, TAX1BP3 (Tax1 binding protein 3). [provided by RefSeq, Mar 2011]

P2RX5-TAX1BP3 (HGNC:49191): (P2RX5-TAX1BP3 readthrough (NMD candidate)) This locus represents naturally occurring read-through transcription between the neighboring P2RX5 (purinergic receptor P2X, ligand-gated ion channel, 5) and TAX1BP3 (Tax1 binding protein 3) genes on chromosome 17. The read-through transcript is a candidate for nonsense-mediated mRNA decay (NMD), and is thus unlikely to produce a protein product. [provided by RefSeq, Mar 2011]

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.047167927).
• BP6: Variant 17-3679768-A-C is Benign according to our data. Variant chr17-3679768-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 3207640.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
P2RX5	NM_002561.4	c.1081T>G	p.Ser361Ala	missense_variant	Exon 11 of 12	ENST00000225328.10	NP_002552.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
P2RX5	ENST00000225328.10	c.1081T>G	p.Ser361Ala	missense_variant	Exon 11 of 12	1	NM_002561.4	ENSP00000225328.5
P2RX5	ENST00000697413.1	c.1147T>G	p.Ser383Ala	missense_variant	Exon 12 of 13			ENSP00000513301.1
P2RX5-TAX1BP3	ENST00000550383.1	n.1081T>G		non_coding_transcript_exon_variant	Exon 11 of 15	2		ENSP00000455681.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Sep 29, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.11
DANN	Benign	0.59
DEOGEN2	Benign	0.019	.;.;.;T;.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0036	N
LIST_S2	Benign	0.17	T;T;T;T;T;T
M_CAP	Benign	0.0030	T
MetaRNN	Benign	0.047	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	-0.55	.;.;.;N;.;.
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.37	.;N;N;N;N;N
REVEL	Benign	0.033
Sift	Benign	0.88	.;T;T;T;T;T
Sift4G	Benign	0.85	T;T;T;T;T;T
Polyphen		0.0	.;B;B;B;.;B
Vest4		0.076
MutPred		0.39		.;.;.;Loss of phosphorylation at S361 (P = 0.0084);.;.;
MVP		0.072
MPC		0.11
ClinPred		0.058	T
GERP RS		-2.4
Varity_R		0.067
gMVP		0.21

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: rs2050187455; hg19: chr17-3583062;