rs145994698
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BS1_Supporting
The NM_001776.6(ENTPD1):āc.1333G>Cā(p.Gly445Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000795 in 1,613,434 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00045 ( 0 hom., cov: 32)
Exomes š: 0.00083 ( 0 hom. )
Consequence
ENTPD1
NM_001776.6 missense
NM_001776.6 missense
Scores
5
14
Clinical Significance
Conservation
PhyloP100: 0.953
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]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000447 (68/152232) while in subpopulation NFE AF= 0.000838 (57/68026). AF 95% confidence interval is 0.000664. There are 0 homozygotes in gnomad4. There are 34 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
ENTPD1 | NM_001776.6 | c.1333G>C | p.Gly445Arg | missense_variant | 10/10 | ENST00000371205.5 | NP_001767.3 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
ENTPD1 | ENST00000371205.5 | c.1333G>C | p.Gly445Arg | missense_variant | 10/10 | 1 | NM_001776.6 | ENSP00000360248.4 | ||
ENSG00000270099 | ENST00000491114.1 | n.171+1322G>C | intron_variant | 5 | ENSP00000473305.1 |
Frequencies
GnomAD3 genomes AF: 0.000447 AC: 68AN: 152114Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000445 AC: 111AN: 249468Hom.: 0 AF XY: 0.000482 AC XY: 65AN XY: 134790
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GnomAD4 exome AF: 0.000832 AC: 1215AN: 1461202Hom.: 0 Cov.: 31 AF XY: 0.000865 AC XY: 629AN XY: 726832
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GnomAD4 genome AF: 0.000447 AC: 68AN: 152232Hom.: 0 Cov.: 32 AF XY: 0.000457 AC XY: 34AN XY: 74414
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Hereditary spastic paraplegia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Genome Diagnostics Laboratory, The Hospital for Sick Children | Jan 17, 2022 | - - |
Hereditary spastic paraplegia 64 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 16, 2022 | This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 445 of the ENTPD1 protein (p.Gly445Arg). This variant is present in population databases (rs145994698, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with ENTPD1-related conditions. ClinVar contains an entry for this variant (Variation ID: 541701). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | not provided | Breakthrough Genomics, Breakthrough Genomics | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Uncertain
DEOGEN2
Benign
.;.;.;T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T;T
M_CAP
Benign
D
MetaRNN
Benign
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;.;M
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Polyphen
P;.;.;P
Vest4
MVP
MPC
0.20
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_AG_spliceai
Position offset: -6
Find out detailed SpliceAI scores and Pangolin per-transcript scores at