Variant chr6-46140371-T-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_014936.5(ENPP4):c.788T>C(p.Ile263Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000116 in 1,596,990 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00012 ( 0 hom. )

Consequence

ENPP4
NM_014936.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.67

Variant links:

Genes affected

ENPP4 (HGNC:3359): (ectonucleotide pyrophosphatase/phosphodiesterase 4) Enables bis(5'-adenosyl)-triphosphatase activity. Involved in positive regulation of blood coagulation and purine ribonucleoside catabolic process. Located in extracellular exosome and membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENPP4 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.3875548).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP4	NM_014936.5 link	c.788T>C	p.Ile263Thr	missense_variant	2/4	ENST00000321037.5	NP_055751.1	Q9Y6X5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP4	ENST00000321037.5 link	c.788T>C	p.Ile263Thr	missense_variant	2/4	1	NM_014936.5	ENSP00000318066.3		Q9Y6X5

Frequencies

GnomAD3 genomes

AF:

0.0000792

AC:

AN:

151512

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000660

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000118

Gnomad OTH

AF:

0.000480

GnomAD3 exomes

AF:

0.0000733

AC:

AN:

231890

Hom.:

AF XY:

0.0000479

AC XY:

AN XY:

125386

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000254

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000852

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000120

AC:

173

AN:

1445478

Hom.:

Cov.:

AF XY:

0.000125

AC XY:

AN XY:

718404

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.000168

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000362

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000143

Gnomad4 OTH exome

AF:

0.0000670

GnomAD4 genome

AF:

0.0000792

AC:

AN:

151512

Hom.:

Cov.:

AF XY:

0.0000946

AC XY:

AN XY:

73988

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.0000660

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000118

Gnomad4 OTH

AF:

0.000480

Alfa

AF:

0.0000963

Hom.:

Bravo

AF:

0.0000680

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 31, 2024

The c.788T>C (p.I263T) alteration is located in exon 2 (coding exon 1) of the ENPP4 gene. This alteration results from a T to C substitution at nucleotide position 788, causing the isoleucine (I) at amino acid position 263 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

0.088

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.21

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.093

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.97

M_CAP

Benign

0.030

MetaRNN

Benign

0.39

MetaSVM

Benign

-0.67

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.48

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.34

Sift

Uncertain

0.0020

Sift4G

Benign

0.16

Polyphen

0.57

Vest4

0.44

MVP

0.80

MPC

0.14

ClinPred

0.22

GERP RS

5.7

Varity_R

0.51

gMVP

0.76

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over