dbSNP rs149497356: ENTPD3:p.Thr253Lys (chr3-40416000-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001248.4(ENTPD3):c.758C>A(p.Thr253Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,794 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign 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. T253M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ENTPD3
NM_001248.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.223

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.16251639).

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.758C>A	p.Thr253Lys	missense	Exon 7 of 11	NP_001239.2	O75355-1
ENTPD3	NM_001291960.2		c.758C>A	p.Thr253Lys	missense	Exon 7 of 11	NP_001278889.1	O75355-1
ENTPD3	NM_001291961.2		c.758C>A	p.Thr253Lys	missense	Exon 7 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.758C>A	p.Thr253Lys	missense	Exon 7 of 11	ENSP00000301825.3	O75355-1
ENTPD3	ENST00000456402.5	TSL:1	c.758C>A	p.Thr253Lys	missense	Exon 7 of 11	ENSP00000401565.1	O75355-1
ENTPD3	ENST00000445129.1	TSL:1	c.758C>A	p.Thr253Lys	missense	Exon 6 of 10	ENSP00000404671.1	O75355-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461794

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727198

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86248

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1111956

Other (OTH)

AF:

0.00

AC:

AN:

60384

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

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

Benign

0.085

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.57

CADD

Benign

9.9

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.030

Eigen

Benign

-0.54

Eigen_PC

Benign

-0.66

FATHMM_MKL

Benign

0.058

LIST_S2

Benign

0.66

M_CAP

Benign

0.0063

MetaRNN

Benign

0.16

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

PhyloP100

0.22

PrimateAI

Benign

0.34

PROVEAN

Benign

-0.57

REVEL

Benign

0.075

Sift

Uncertain

0.024

Sift4G

Benign

0.55

Polyphen

0.93

Vest4

0.41

MutPred

0.49

Gain of ubiquitination at T253 (P = 0.0289)

MVP

0.18

MPC

0.072

ClinPred

0.26

GERP RS

2.3

Varity_R

0.12

gMVP

0.65

Mutation Taster

=92/8

polymorphism

(source)

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

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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