9-137048803-T-C

Variant names:

• chr9-137048803-T-C
• rs1728473290
• NM_203468.3:c.1342A>G

Variant summary

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

The NM_203468.3(ENTPD2):​c.1342A>G​(p.Ile448Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000701 in 1,425,922 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: ENTPD2 NM_203468.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.86

Genes affected

ENTPD2 (HGNC:3364): (ectonucleoside triphosphate diphosphohydrolase 2) The protein encoded by this gene is the type 2 enzyme of the ecto-nucleoside triphosphate diphosphohydrolase family (E-NTPDase). E-NTPDases are a family of ecto-nucleosidases that hydrolyze 5'-triphosphates. This ecto-ATPase is an integral membrane protein. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Jul 2008]

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=0.1673556).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3	c.1342A>G	p.Ile448Val	missense_variant	Exon 9 of 9	ENST00000355097.7	NP_982293.1
ENTPD2	NM_001246.4	c.1273A>G	p.Ile425Val	missense_variant	Exon 9 of 9		NP_001237.1
ENTPD2	XM_011519212.3	c.1033A>G	p.Ile345Val	missense_variant	Exon 8 of 8		XP_011517514.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD2	ENST00000355097.7	c.1342A>G	p.Ile448Val	missense_variant	Exon 9 of 9	1	NM_203468.3	ENSP00000347213.2
ENTPD2	ENST00000312665.7	c.1273A>G	p.Ile425Val	missense_variant	Exon 9 of 9	1		ENSP00000312494.5
ENTPD2	ENST00000460614.1	n.731A>G		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.01e-7 AC: 1 AN: 1425922 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 705514

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.0000170

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 11, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1342A>G (p.I448V) alteration is located in exon 9 (coding exon 9) of the ENTPD2 gene. This alteration results from a A to G substitution at nucleotide position 1342, causing the isoleucine (I) at amino acid position 448 to be replaced by a valine (V). 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	0.25
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T;.
Eigen	Benign	0.035
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.80	T;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.0	M;.
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-0.87	N;N
REVEL	Benign	0.12
Sift	Benign	0.052	T;T
Sift4G	Uncertain	0.013	D;D
Polyphen		0.37	B;P
Vest4		0.11
MutPred		0.59		Gain of disorder (P = 0.153);.;
MVP		0.47
MPC		0.050
ClinPred		0.92	D
GERP RS		2.6
Varity_R		0.14
gMVP		0.60

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: rs1728473290; hg19: chr9-139943255;