Genetic Variant ENTPD8:p.Leu399Pro (chr9-137435304-A-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_001033113.2(ENTPD8):c.1196T>C(p.Leu399Pro) variant causes a missense change. The variant allele was found at a frequency of 0.000000685 in 1,459,924 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 (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

ENTPD8
NM_001033113.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.84

Publications

0 publications found

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:

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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, 0.961

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD8	NM_001033113.2 link	c.1196T>C	p.Leu399Pro	missense_variant	Exon 9 of 10	ENST00000371506.7	NP_001028285.1	Q5MY95-1
ENTPD8	NM_198585.3 link	c.1085T>C	p.Leu362Pro	missense_variant	Exon 8 of 9		NP_940987.2	Q5MY95-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENTPD8	ENST00000371506.7 link	c.1196T>C	p.Leu399Pro	missense_variant	Exon 9 of 10	5	NM_001033113.2	ENSP00000360561.2	Q5MY95-1
ENTPD8	ENST00000344119.6 link	c.1085T>C	p.Leu362Pro	missense_variant	Exon 8 of 9	1		ENSP00000344089.2	Q5MY95-2
ENTPD8	ENST00000461823.1 link	n.1994T>C		non_coding_transcript_exon_variant	Exon 7 of 8	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000402

AC:

AN:

248576

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS 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:

6.85e-7

AC:

AN:

1459924

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726286

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33466

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51942

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5642

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111786

Other (OTH)

AF:

0.00

AC:

AN:

60342

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Oct 25, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1196T>C (p.L399P) alteration is located in exon 9 (coding exon 8) of the ENTPD8 gene. This alteration results from a T to C substitution at nucleotide position 1196, causing the leucine (L) at amino acid position 399 to be replaced by a proline (P). 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

Pathogenic

0.80

BayesDel_addAF

Benign

-0.075

BayesDel_noAF

Benign

-0.24

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

.;T;T

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.36

LIST_S2

Benign

0.66

T;T;.

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.96

D;D;D

MetaSVM

Benign

-0.74

MutationAssessor

Pathogenic

3.6

.;H;H

PhyloP100

3.8

PrimateAI

Uncertain

0.56

PROVEAN

Pathogenic

-5.4

D;D;D

REVEL

Benign

0.19

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0010

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.66

MutPred

0.80

.;Gain of disorder (P = 0.0178);Gain of disorder (P = 0.0178);

MVP

0.23

MPC

0.47

ClinPred

0.99

GERP RS

4.1

Varity_R

0.98

gMVP

0.95

Mutation Taster

=66/34

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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chr9-137435304-A-G

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over