9-137049024-C-T

Variant names:

• chr9-137049024-C-T
• rs1407093280
• NM_203468.3:c.1201G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_203468.3(ENTPD2):​c.1201G>A​(p.Gly401Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000325 in 1,536,966 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 0.0000066 (0 hom., cov: 34)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: ENTPD2 NM_203468.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.377
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.19136691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD2	NM_203468.3	c.1201G>A	p.Gly401Arg	missense_variant	Exon 8 of 9	ENST00000355097.7	NP_982293.1
ENTPD2	XM_011519212.3	c.892G>A	p.Gly298Arg	missense_variant	Exon 7 of 8		XP_011517514.1
ENTPD2	NM_001246.4	c.1150-18G>A		intron_variant	Intron 7 of 8		NP_001237.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD2	ENST00000355097.7	c.1201G>A	p.Gly401Arg	missense_variant	Exon 8 of 9	1	NM_203468.3	ENSP00000347213.2
ENTPD2	ENST00000460614.1	n.590G>A		non_coding_transcript_exon_variant	Exon 1 of 2	1
ENTPD2	ENST00000312665.7	c.1150-18G>A		intron_variant	Intron 7 of 8	1		ENSP00000312494.5

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000289 AC: 4 AN: 1384736 Hom.: 0 Cov.: 68 AF XY: 0.00000439 AC XY: 3 AN XY: 683310

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31300

American (AMR) AF: 0.00 AC: 0 AN: 35438

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25056

East Asian (EAS) AF: 0.00 AC: 0 AN: 35552

South Asian (SAS) AF: 0.00 AC: 0 AN: 79182

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 37330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5604

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1077538

Other (OTH) AF: 0.00 AC: 0 AN: 57736

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.026173), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152230 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41462

American (AMR) AF: 0.00 AC: 0 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 20, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1201G>A (p.G401R) alteration is located in exon 8 (coding exon 8) of the ENTPD2 gene. This alteration results from a G to A substitution at nucleotide position 1201, causing the glycine (G) at amino acid position 401 to be replaced by an arginine (R). 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	Uncertain	0.45
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.017	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.63
FATHMM_MKL	Benign	0.092	N
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.041	D
MetaRNN	Benign	0.19	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L
PhyloP100		-0.38
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-0.94	N
REVEL	Benign	0.11
Sift	Benign	0.20	T
Sift4G	Benign	0.29	T
Polyphen		0.99	D
Vest4		0.25
MutPred		0.65		Gain of MoRF binding (P = 0.0081);
MVP		0.35
MPC		0.082
ClinPred		0.19	T
GERP RS		0.32
Varity_R		0.20
gMVP		0.74
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs1407093280; hg19: chr9-139943476;