rs1555301559

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000371205.5(ENTPD1):ā€‹c.177C>Gā€‹(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 (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000014 ( 0 hom. )

Consequence

ENTPD1
ENST00000371205.5 missense

Scores

5
9
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.457
Variant links:
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)

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ACMG classification

Classification made for transcript

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
ENTPD1NM_001776.6 linkuse as main transcriptc.177C>G p.His59Gln missense_variant 3/10 ENST00000371205.5 NP_001767.3
ENTPD1-AS1NR_038444.1 linkuse as main transcriptn.533+7669G>C intron_variant, non_coding_transcript_variant

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
ENTPD1ENST00000371205.5 linkuse as main transcriptc.177C>G p.His59Gln missense_variant 3/101 NM_001776.6 ENSP00000360248 P1P49961-1
ENST00000433113.1 linkuse as main transcriptn.260+5956C>G intron_variant, non_coding_transcript_variant 2
ENTPD1-AS1ENST00000669711.1 linkuse as main transcriptn.443+36795G>C intron_variant, non_coding_transcript_variant

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
show subpopulations
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
LINK: link

Submissions by phenotype

Hereditary spastic paraplegia 64 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2020In 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
MutationTaster
Benign
1.0
D;D;D;D;D;D;D
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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555301559; hg19: chr10-97599480; API