rs149326648

Positions:

• chr10-95847652-C-G
• chr10-95847652-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001776.6(ENTPD1):​c.1020C>G​(p.Tyr340*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ENTPD1 NM_001776.6 stop_gained
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 1.31

Genes affected

ENTPD1 (HGNC:3363): (ectonucleoside triphosphate diphosphohydrolase 1) The protein encoded by this gene is a plasma membrane protein that hydrolyzes extracellular ATP and ADP to AMP. Inhibition of this protein's activity may confer anticancer benefits. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2015]

ENTPD1-AS1 (HGNC:45203): (ENTPD1 antisense RNA 1)

ENSG00000240527 (HGNC:):

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-95847652-C-G is Pathogenic according to our data. Variant chr10-95847652-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 2129367.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENTPD1	NM_001776.6	c.1020C>G	p.Tyr340*	stop_gained	7/10	ENST00000371205.5	NP_001767.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENTPD1	ENST00000371205.5	c.1020C>G	p.Tyr340*	stop_gained	7/10	1	NM_001776.6	ENSP00000360248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251468 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135912

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000879

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 64 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 29, 2022

For these reasons, this variant has been classified as Pathogenic. This variant has not been reported in the literature in individuals affected with ENTPD1-related conditions. This variant is present in population databases (rs149326648, gnomAD 0.0009%). This sequence change creates a premature translational stop signal (p.Tyr340*) in the ENTPD1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in ENTPD1 are known to be pathogenic (PMID: 24482476, 29691679). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.60	D
BayesDel_noAF	Pathogenic	0.54
CADD	Pathogenic	34
DANN	Uncertain	1.0
Eigen	Uncertain	0.24
Eigen_PC	Benign	0.046
FATHMM_MKL	Uncertain	0.88	D
Vest4		0.53
GERP RS		2.8

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: rs149326648; hg19: chr10-97607409;