Genetic Variant ENTPD8:p.Ala458Ser (chr9-137435030-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001033113.2(ENTPD8):c.1372G>T(p.Ala458Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000036 in 1,612,774 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00019 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000020 ( 0 hom. )

Consequence

ENTPD8
NM_001033113.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.406

Variant links:

Genes affected

ENTPD8 (HGNC:24860): (ectonucleoside triphosphate diphosphohydrolase 8) Predicted to enable guanosine-diphosphatase activity and uridine-diphosphatase activity. Predicted to be involved in nucleoside diphosphate catabolic process. Predicted to act upstream of or within nucleoside diphosphate biosynthetic process and nucleoside monophosphate biosynthetic process. Predicted to be integral component of membrane. Predicted to be active in plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENTPD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.013117552).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD8	NM_001033113.2 link	c.1372G>T	p.Ala458Ser	missense_variant	Exon 10 of 10	ENST00000371506.7	NP_001028285.1	Q5MY95-1
ENTPD8	NM_198585.3 link	c.1261G>T	p.Ala421Ser	missense_variant	Exon 9 of 9		NP_940987.2	Q5MY95-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENTPD8	ENST00000371506.7 link	c.1372G>T	p.Ala458Ser	missense_variant	Exon 10 of 10	5	NM_001033113.2	ENSP00000360561.2	Q5MY95-1
ENTPD8	ENST00000344119.6 link	c.1261G>T	p.Ala421Ser	missense_variant	Exon 9 of 9	1		ENSP00000344089.2	Q5MY95-2
ENTPD8	ENST00000461823.1 link	n.2170G>T		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes

AF:

0.000190

AC:

AN:

152236

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000700

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000483

AC:

AN:

248454

Hom.:

AF XY:

0.0000296

AC XY:

AN XY:

135030

show subpopulations

Gnomad AFR exome

AF:

0.000692

Gnomad AMR exome

AF:

0.0000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000199

AC:

AN:

1460420

Hom.:

Cov.:

AF XY:

0.0000165

AC XY:

AN XY:

726574

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.0000224

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:

0.00000270

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.000190

AC:

AN:

152354

Hom.:

Cov.:

AF XY:

0.000188

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000697

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000858

Hom.:

Bravo

AF:

0.000276

ESP6500AA

AF:

0.000910

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000826

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1372G>T (p.A458S) alteration is located in exon 10 (coding exon 9) of the ENTPD8 gene. This alteration results from a G to T substitution at nucleotide position 1372, causing the alanine (A) at amino acid position 458 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Benign

-0.57

BayesDel_noAF

Benign

-0.70

CADD

Benign

3.2

DANN

Benign

0.78

DEOGEN2

Benign

0.019

.;T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-0.95

FATHMM_MKL

Benign

0.16

LIST_S2

Benign

0.64

T;T;.

M_CAP

Benign

0.021

MetaRNN

Benign

0.013

T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.4

.;L;L

PrimateAI

Benign

0.27

PROVEAN

Benign

-0.43

N;N;N

REVEL

Benign

0.014

Sift

Benign

0.85

T;T;T

Sift4G

Benign

0.69

T;T;T

Polyphen

0.066

B;B;B

Vest4

0.14

MVP

0.014

MPC

0.066

ClinPred

0.010

GERP RS

3.1

Varity_R

0.041

gMVP

0.17

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over