rs975235613

Variant names:

• chr9-137048716-C-T
• rs975235613
• NM_203468.3:c.1429G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_203468.3(ENTPD2):​c.1429G>A​(p.Ala477Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000809 in 1,606,244 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000069 (0 hom.)
• Consequence: ENTPD2 NM_203468.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.181
• Publications: 0 publications found

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05766961).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3	c.1429G>A	p.Ala477Thr	missense_variant	Exon 9 of 9	ENST00000355097.7	NP_982293.1
ENTPD2	NM_001246.4	c.1360G>A	p.Ala454Thr	missense_variant	Exon 9 of 9		NP_001237.1
ENTPD2	XM_011519212.3	c.1120G>A	p.Ala374Thr	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.1429G>A	p.Ala477Thr	missense_variant	Exon 9 of 9	1	NM_203468.3	ENSP00000347213.2
ENTPD2	ENST00000312665.7	c.1360G>A	p.Ala454Thr	missense_variant	Exon 9 of 9	1		ENSP00000312494.5
ENTPD2	ENST00000460614.1	n.818G>A		non_coding_transcript_exon_variant	Exon 2 of 2	1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

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

GnomAD4 exome AF: 0.00000688 AC: 10 AN: 1454110 Hom.: 0 Cov.: 39 AF XY: 0.00000553 AC XY: 4 AN XY: 722922

African (AFR) AF: 0.0000300 AC: 1 AN: 33378

American (AMR) AF: 0.00 AC: 0 AN: 44120

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39538

South Asian (SAS) AF: 0.00 AC: 0 AN: 85264

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51002

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5742

European-Non Finnish (NFE) AF: 0.00000721 AC: 8 AN: 1109176

Other (OTH) AF: 0.00 AC: 0 AN: 60054

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152134 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74330

African (AFR) AF: 0.0000724 AC: 3 AN: 41418

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1429G>A (p.A477T) alteration is located in exon 9 (coding exon 9) of the ENTPD2 gene. This alteration results from a G to A substitution at nucleotide position 1429, causing the alanine (A) at amino acid position 477 to be replaced by a threonine (T). 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	0.096
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.65
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.050	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.13	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.058	T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	0.0	N;.
PhyloP100		-0.18
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-0.98	N;N
REVEL	Benign	0.0060
Sift	Benign	0.23	T;T
Sift4G	Benign	0.40	T;T
Polyphen		0.010	B;B
Vest4		0.10
MutPred		0.31		Loss of stability (P = 0.3792);.;
MVP		0.28
MPC		0.086
ClinPred		0.074	T
GERP RS		0.54
Varity_R		0.040
gMVP		0.72
Mutation Taster		=94/6	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs975235613; hg19: chr9-139943168;