3-40411913-G-A

Variant names:

• chr3-40411913-G-A
• rs771858873
• NM_001248.4:c.388G>A

Variant summary

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

The NM_001248.4(ENTPD3):​c.388G>A​(p.Gly130Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000496 in 1,612,032 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: ENTPD3 NM_001248.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.103
• Publications: 2 publications found

Genes affected

ENTPD3 (HGNC:3365): (ectonucleoside triphosphate diphosphohydrolase 3) This gene encodes a plasma membrane-bound divalent cation-dependent E-type nucleotidase. The encoded protein is involved in the regulation of extracellular levels of ATP by hydrolysis of it and other nucleotides. Multiple transcript variants have been described. [provided by RefSeq, May 2014]

ENTPD3-AS1 (HGNC:):

ENTPD3-AS1 (HGNC:26710): (ENTPD3 antisense RNA 1)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001248.4. 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
	ENTPD3	NM_001248.4	MANE Select	c.388G>A	p.Gly130Arg	missense	Exon 5 of 11	NP_001239.2	O75355-1
	ENTPD3	NM_001291960.2		c.388G>A	p.Gly130Arg	missense	Exon 5 of 11	NP_001278889.1	O75355-1
	ENTPD3	NM_001291961.2		c.388G>A	p.Gly130Arg	missense	Exon 5 of 11	NP_001278890.1	O75355-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENTPD3	ENST00000301825.8	TSL:1 MANE Select	c.388G>A	p.Gly130Arg	missense	Exon 5 of 11	ENSP00000301825.3	O75355-1
	ENTPD3	ENST00000456402.5	TSL:1	c.388G>A	p.Gly130Arg	missense	Exon 5 of 11	ENSP00000401565.1	O75355-1
	ENTPD3	ENST00000445129.1	TSL:1	c.388G>A	p.Gly130Arg	missense	Exon 4 of 10	ENSP00000404671.1	O75355-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

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

GnomAD2 exomes AF: 0.00000402 AC: 1 AN: 248476 AF XY: 0.00000745

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000463

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000411 AC: 6 AN: 1460016 Hom.: 0 Cov.: 31 AF XY: 0.00000826 AC XY: 6 AN XY: 726198

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26118

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 85718

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111248

Other (OTH) AF: 0.00 AC: 0 AN: 60336

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 152016 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74242

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

African (AFR) AF: 0.0000483 AC: 2 AN: 41404

American (AMR) AF: 0.00 AC: 0 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4802

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68004

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

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.062
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.78
CADD	Benign	0.20
DANN	Benign	0.40
DEOGEN2	Benign	0.021	T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.6
FATHMM_MKL	Benign	0.026	N
LIST_S2	Benign	0.17	T
M_CAP	Benign	0.0038	T
MetaRNN	Benign	0.022	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-0.76	N
PhyloP100		0.10
PrimateAI	Benign	0.26	T
PROVEAN	Benign	1.4	N
REVEL	Benign	0.020
Sift	Benign	0.91	T
Sift4G	Benign	0.56	T
Polyphen		0.027	B
Vest4		0.16
MutPred		0.42		Gain of solvent accessibility (P = 0.0037)
MVP		0.16
MPC		0.070
ClinPred		0.032	T
GERP RS		-5.8
Varity_R		0.040
gMVP		0.35
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.25		Position offset: 49

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

Other links and lift over

dbSNP: rs771858873; hg19: chr3-40453404; COSMIC: COSV57194362;