Genetic Variant ENTPD3:p.Thr139Arg (chr3-40411941-C-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_001248.4(ENTPD3):c.416C>G(p.Thr139Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,724 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T139M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

ENTPD3
NM_001248.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.21

Publications

0 publications found

Variant links:

Genes affected

ENTPD3 (HGNC:3365): (ectonucleoside triphosphate diphosphohydrolase 3) This gene encodes a plasma membrane-bound divalent cation-dependent E-type nucleotidase. The encoded protein is involved in the regulation of extracellular levels of ATP by hydrolysis of it and other nucleotides. Multiple transcript variants have been described. [provided by RefSeq, May 2014]

ENTPD3 links:

ENTPD3-AS1 (HGNC:):

ENTPD3-AS1 links:

ENTPD3-AS1 (HGNC:26710): (ENTPD3 antisense RNA 1)

ENTPD3-AS1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.97

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001248.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENTPD3	NM_001248.4	MANE Select	c.416C>G	p.Thr139Arg	missense	Exon 5 of 11	NP_001239.2	O75355-1
ENTPD3	NM_001291960.2		c.416C>G	p.Thr139Arg	missense	Exon 5 of 11	NP_001278889.1	O75355-1
ENTPD3	NM_001291961.2		c.416C>G	p.Thr139Arg	missense	Exon 5 of 11	NP_001278890.1	O75355-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENTPD3	ENST00000301825.8	TSL:1 MANE Select	c.416C>G	p.Thr139Arg	missense	Exon 5 of 11	ENSP00000301825.3	O75355-1
ENTPD3	ENST00000456402.5	TSL:1	c.416C>G	p.Thr139Arg	missense	Exon 5 of 11	ENSP00000401565.1	O75355-1
ENTPD3	ENST00000445129.1	TSL:1	c.416C>G	p.Thr139Arg	missense	Exon 4 of 10	ENSP00000404671.1	O75355-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458724

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725504

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33434

American (AMR)

AF:

0.00

AC:

AN:

44152

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39570

South Asian (SAS)

AF:

0.00

AC:

AN:

85352

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53372

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5708

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1110718

Other (OTH)

AF:

0.00

AC:

AN:

60302

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.29

BayesDel_noAF

Pathogenic

0.18

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.41

Eigen

Pathogenic

1.0

Eigen_PC

Pathogenic

0.92

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.89

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.97

MetaSVM

Uncertain

-0.13

MutationAssessor

Pathogenic

3.6

PhyloP100

7.2

PrimateAI

Uncertain

0.61

PROVEAN

Pathogenic

-5.9

REVEL

Pathogenic

0.66

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.98

MutPred

0.84

Gain of MoRF binding (P = 0.0037)

MVP

0.78

MPC

0.39

ClinPred

1.0

GERP RS

5.6

Varity_R

0.94

gMVP

0.96

Mutation Taster

=35/65

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.39

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.39

Position offset: 21

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over