rs1555301559

Positions:

• chr10-95839723-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001776.6(ENTPD1):​c.177C>G​(p.His59Gln) 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 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ENTPD1 NM_001776.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.457

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.928

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENTPD1	NM_001776.6	c.177C>G	p.His59Gln	missense_variant	3/10	ENST00000371205.5	NP_001767.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENTPD1	ENST00000371205.5	c.177C>G	p.His59Gln	missense_variant	3/10	1	NM_001776.6	ENSP00000360248.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461880 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary spastic paraplegia 64 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 07, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with ENTPD1-related disease. This variant is not present in population databases (ExAC no frequency). This sequence change replaces histidine with glutamine at codon 59 of the ENTPD1 protein (p.His59Gln). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and glutamine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.41	.;.;T
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Uncertain	0.92	D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.93	D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.8	.;.;H
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-7.1	D;D;D
REVEL	Uncertain	0.32
Sift	Pathogenic	0.0	D;D;D
Sift4G	Uncertain	0.011	D;D;D
Polyphen		1.0	D;.;D
Vest4		0.73
MutPred		0.85		.;.;Gain of sheet (P = 0.1208);
MVP		0.57
MPC		0.67
ClinPred		1.0	D
GERP RS		0.62
Varity_R		0.88
gMVP		0.87

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: rs1555301559; hg19: chr10-97599480;