8-23435460-C-G

Variant names:

• chr8-23435460-C-G
• rs143860868
• NM_004901.5:c.1392G>C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004901.5(ENTPD4):​c.1392G>C​(p.Lys464Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000517 in 1,613,926 control chromosomes in the GnomAD database, including 3 homozygotes. 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: 𝑓 0.00042 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00053 (2 hom.)
• Consequence: ENTPD4 NM_004901.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.35

Genes affected

ENTPD4 (HGNC:14573): (ectonucleoside triphosphate diphosphohydrolase 4) This gene encodes a member of the apyrase protein family. Apyrases are enzymes that catalyze the hydrolysis of nucleotide diphosphates and triphosphates in a calcium or magnesium-dependent manner. The encoded protein is an endo-apyrase and may play a role in salvaging nucleotides from lysosomes. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene, and these isoforms may differ in divalent cation dependence and substrate specificity. [provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039490283).
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENTPD4	NM_004901.5	c.1392G>C	p.Lys464Asn	missense_variant	Exon 11 of 13	ENST00000358689.9	NP_004892.1
ENTPD4	NM_001128930.3	c.1368G>C	p.Lys456Asn	missense_variant	Exon 11 of 13		NP_001122402.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENTPD4	ENST00000358689.9	c.1392G>C	p.Lys464Asn	missense_variant	Exon 11 of 13	1	NM_004901.5	ENSP00000351520.4

Frequencies

GnomAD3 genomes AF: 0.000414 AC: 63 AN: 152218 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000864

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000588

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000720 AC: 181 AN: 251380 Hom.: 2 AF XY: 0.000810 AC XY: 110 AN XY: 135866

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000810

Gnomad ASJ exome AF: 0.00129

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00150

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000739

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000528 AC: 771 AN: 1461590 Hom.: 2 Cov.: 30 AF XY: 0.000579 AC XY: 421 AN XY: 727116

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000827

Gnomad4 ASJ exome AF: 0.00107

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.0000374

Gnomad4 NFE exome AF: 0.000471

Gnomad4 OTH exome AF: 0.000662

GnomAD4 genome AF: 0.000420 AC: 64 AN: 152336 Hom.: 1 Cov.: 33 AF XY: 0.000376 AC XY: 28 AN XY: 74488

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000864

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000603

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000663 Hom.: 0

Bravo AF: 0.000412

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00128 AC: 11

ExAC AF: 0.000741 AC: 90

EpiCase AF: 0.00142

EpiControl AF: 0.000830

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 13, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1392G>C (p.K464N) alteration is located in exon 1 (coding exon 1) of the ENTPD4 gene. This alteration results from a G to C substitution at nucleotide position 1392, causing the lysine (K) at amino acid position 464 to be replaced by an asparagine (N). 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	0.34
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.64
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0020	.;T;T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.0034
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.68	T;T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.039	T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.49	.;.;N;.
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.30	T;T;T;T
Sift4G	Benign	0.21	T;T;T;T
Polyphen		0.0040, 0.0060, 0.0020	.;B;B;B
Vest4		0.47, 0.47
MutPred		0.47		.;.;Loss of MoRF binding (P = 0.0471);.;
MVP		0.30
MPC		0.31
ClinPred		0.081	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.27
gMVP		0.53

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: rs143860868; hg19: chr8-23292973;