rs1049099453

Variant names:

• chr9-137435056-G-A
• rs1049099453
• NM_001033113.2:c.1346C>T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001033113.2(ENTPD8):​c.1346C>T​(p.Thr449Ile) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: ENTPD8 NM_001033113.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.09

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD8	NM_001033113.2	c.1346C>T	p.Thr449Ile	missense_variant	Exon 10 of 10	ENST00000371506.7	NP_001028285.1
ENTPD8	NM_198585.3	c.1235C>T	p.Thr412Ile	missense_variant	Exon 9 of 9		NP_940987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD8	ENST00000371506.7	c.1346C>T	p.Thr449Ile	missense_variant	Exon 10 of 10	5	NM_001033113.2	ENSP00000360561.2
ENTPD8	ENST00000344119.6	c.1235C>T	p.Thr412Ile	missense_variant	Exon 9 of 9	1		ENSP00000344089.2
ENTPD8	ENST00000461823.1	n.2144C>T		non_coding_transcript_exon_variant	Exon 8 of 8	2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 22, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1346C>T (p.T449I) alteration is located in exon 10 (coding exon 9) of the ENTPD8 gene. This alteration results from a C to T substitution at nucleotide position 1346, causing the threonine (T) at amino acid position 449 to be replaced by an isoleucine (I). 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	0.95
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Benign	-0.32
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.19	.;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.97	D;D;.
M_CAP	Benign	0.051	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Benign	-0.95	T
MutationAssessor	Uncertain	2.8	.;M;M
PrimateAI	Uncertain	0.63	T
PROVEAN	Pathogenic	-5.4	D;D;D
REVEL	Uncertain	0.31
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.77
MutPred		0.80		.;Loss of loop (P = 0.0512);Loss of loop (P = 0.0512);
MVP		0.21
MPC		0.40
ClinPred		1.0	D
GERP RS		5.1
Varity_R		0.92
gMVP		0.92

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

Other links and lift over

dbSNP: rs1049099453; hg19: chr9-140329508;