9-137435807-G-A

Variant names:

• chr9-137435807-G-A
• rs181530826
• NM_001033113.2:c.1073C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001033113.2(ENTPD8):​c.1073C>T​(p.Thr358Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00059 in 1,613,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00061 (0 hom.)
• Consequence: ENTPD8 NM_001033113.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.27

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2174659).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD8	NM_001033113.2	c.1073C>T	p.Thr358Ile	missense_variant	Exon 8 of 10	ENST00000371506.7	NP_001028285.1
ENTPD8	NM_198585.3	c.1050+206C>T		intron_variant	Intron 7 of 8		NP_940987.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD8	ENST00000371506.7	c.1073C>T	p.Thr358Ile	missense_variant	Exon 8 of 10	5	NM_001033113.2	ENSP00000360561.2
ENTPD8	ENST00000344119.6	c.1050+206C>T		intron_variant	Intron 7 of 8	1		ENSP00000344089.2
ENTPD8	ENST00000461823.1	n.1871C>T		non_coding_transcript_exon_variant	Exon 6 of 8	2

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152240 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000402 AC: 100 AN: 249020 Hom.: 0 AF XY: 0.000443 AC XY: 60 AN XY: 135364

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000348

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000490

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000612

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000606 AC: 885 AN: 1461246 Hom.: 0 Cov.: 33 AF XY: 0.000620 AC XY: 451 AN XY: 726964

Gnomad4 AFR exome AF: 0.000119

Gnomad4 AMR exome AF: 0.000335

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000698

Gnomad4 OTH exome AF: 0.000513

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152358 Hom.: 0 Cov.: 33 AF XY: 0.000403 AC XY: 30 AN XY: 74498

Gnomad4 AFR AF: 0.0000240

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000567 Hom.: 0

Bravo AF: 0.000450

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000706 AC: 6

ExAC AF: 0.000429 AC: 52

EpiCase AF: 0.000654

EpiControl AF: 0.000711

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1073C>T (p.T358I) alteration is located in exon 8 (coding exon 7) of the ENTPD8 gene. This alteration results from a C to T substitution at nucleotide position 1073, causing the threonine (T) at amino acid position 358 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	Benign	0.31
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.44
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.074	T;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.12
FATHMM_MKL	Benign	0.18	N
LIST_S2	Benign	0.78	T;.
M_CAP	Benign	0.028	D
MetaRNN	Benign	0.22	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	M;M
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.13
Sift	Uncertain	0.0050	D;D
Sift4G	Benign	0.086	T;T
Polyphen		0.77	P;P
Vest4		0.70
MVP		0.12
MPC		0.18
ClinPred		0.076	T
GERP RS		4.2
Varity_R		0.41
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs181530826; hg19: chr9-140330259;