NM_203468.3:c.1226T>G

Variant names:

• chr9-137048999-A-C
• rs1044540301
• NM_203468.3:c.1226T>G

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_203468.3(ENTPD2):​c.1226T>G​(p.Leu409Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000722 in 1,385,276 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L409P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ENTPD2 NM_203468.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.41
• 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_pathogenic. The variant received 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.972

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_203468.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENTPD2	NM_203468.3	MANE Select	c.1226T>G	p.Leu409Arg	missense	Exon 8 of 9	NP_982293.1	Q9Y5L3-1
	ENTPD2	NM_001246.4		c.1157T>G	p.Leu386Arg	missense	Exon 8 of 9	NP_001237.1	Q9Y5L3-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENTPD2	ENST00000355097.7	TSL:1 MANE Select	c.1226T>G	p.Leu409Arg	missense	Exon 8 of 9	ENSP00000347213.2	Q9Y5L3-1
	ENTPD2	ENST00000312665.7	TSL:1	c.1157T>G	p.Leu386Arg	missense	Exon 8 of 9	ENSP00000312494.5	Q9Y5L3-2
	ENTPD2	ENST00000460614.1	TSL:1	n.615T>G		non_coding_transcript_exon	Exon 1 of 2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome AF: 7.22e-7 AC: 1 AN: 1385276 Hom.: 0 Cov.: 67 AF XY: 0.00000146 AC XY: 1 AN XY: 683494

⚠️ 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: 31262

American (AMR) AF: 0.00 AC: 0 AN: 35484

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25050

East Asian (EAS) AF: 0.00 AC: 0 AN: 35480

South Asian (SAS) AF: 0.00 AC: 0 AN: 79154

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38274

Middle Eastern (MID) AF: 0.000179 AC: 1 AN: 5588

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1077254

Other (OTH) AF: 0.00 AC: 0 AN: 57730

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.30	T
Eigen	Uncertain	0.41
Eigen_PC	Benign	0.21
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.85	T
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Benign	-0.30	T
MutationAssessor	Pathogenic	3.8	H
PhyloP100		2.4
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Polyphen		0.99	D
Vest4		0.90
MutPred		0.92		Gain of methylation at L409 (P = 0.0169)
MVP		0.70
MPC		0.39
ClinPred		0.98	D
GERP RS		3.5
Varity_R		0.89
gMVP		0.97
Mutation Taster		=60/40	polymorphism

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

Other links and lift over

dbSNP: rs1044540301; hg19: chr9-139943451;