Variant 6-46141052-A-G details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1PM2BP4_Moderate

The NM_014936.5(ENPP4):c.827A>G(p.Asn276Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.0000372 in 1,558,686 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000046 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000036 ( 0 hom. )

Consequence

ENPP4
NM_014936.5 missense, splice_region

Scores

Splicing: ADA: 0.003600

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.69

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 2 ACMG points.

PM1

In a glycosylation_site N-linked (GlcNAc...) asparagine (size 0) in uniprot entity ENPP4_HUMAN

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.12924516).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP4	NM_014936.5 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	3/4	ENST00000321037.5	NP_055751.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP4	ENST00000321037.5 linkuse as main transcript	c.827A>G	p.Asn276Ser	missense_variant, splice_region_variant	3/4	1	NM_014936.5	ENSP00000318066	P1

Frequencies

GnomAD3 genomes

AF:

0.0000463

AC:

AN:

151236

Hom.:

Cov.:

show subpopulations

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:

0.0000887

Gnomad OTH

AF:

0.000482

GnomAD3 exomes

AF:

0.0000277

AC:

AN:

216242

Hom.:

AF XY:

0.0000254

AC XY:

AN XY:

118186

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000123

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:

0.0000292

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000362

AC:

AN:

1407332

Hom.:

Cov.:

AF XY:

0.0000358

AC XY:

AN XY:

699064

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000118

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000414

Gnomad4 OTH exome

AF:

0.0000345

GnomAD4 genome

AF:

0.0000462

AC:

AN:

151354

Hom.:

Cov.:

AF XY:

0.0000541

AC XY:

AN XY:

73964

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000887

Gnomad4 OTH

AF:

0.000477

Alfa

AF:

0.0000851

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.0000247

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

May 11, 2022

The c.827A>G (p.N276S) alteration is located in exon 3 (coding exon 2) of the ENPP4 gene. This alteration results from a A to G substitution at nucleotide position 827, causing the asparagine (N) at amino acid position 276 to be replaced by a serine (S). 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

0.076

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.44

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.013

Eigen

Uncertain

0.21

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.86

M_CAP

Benign

0.030

MetaRNN

Benign

0.13

MetaSVM

Benign

-0.73

MutationAssessor

Benign

1.6

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Benign

-0.80

REVEL

Benign

0.21

Sift

Benign

0.13

Sift4G

Benign

0.15

Polyphen

0.68

Vest4

0.11

MVP

0.74

MPC

0.084

ClinPred

0.18

GERP RS

6.1

Varity_R

0.28

gMVP

0.56

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.0036

dbscSNV1_RF

Benign

0.090

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