Variant 6-131808108-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_006208.3(ENPP1):c.73G>C(p.Ala25Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000652 in 1,226,148 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000065 ( 0 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.14

Variant links:

Genes affected

ENPP1 (HGNC:3356): (ectonucleotide pyrophosphatase/phosphodiesterase 1) This gene is a member of the ecto-nucleotide pyrophosphatase/phosphodiesterase (ENPP) family. The encoded protein is a type II transmembrane glycoprotein comprising two identical disulfide-bonded subunits. This protein has broad specificity and cleaves a variety of substrates, including phosphodiester bonds of nucleotides and nucleotide sugars and pyrophosphate bonds of nucleotides and nucleotide sugars. This protein may function to hydrolyze nucleoside 5' triphosphates to their corresponding monophosphates and may also hydrolyze diadenosine polyphosphates. Mutations in this gene have been associated with 'idiopathic' infantile arterial calcification, ossification of the posterior longitudinal ligament of the spine (OPLL), and insulin resistance. [provided by RefSeq, Jul 2008]

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3 link	c.73G>C	p.Ala25Pro	missense_variant	1/25	ENST00000647893.1	NP_006199.2	P22413

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
ENPP1	ENST00000647893.1 link	c.73G>C	p.Ala25Pro	missense_variant	1/25		NM_006208.3	ENSP00000498074.1	P22413
ENPP1	ENST00000486853.1 link	n.93G>C		non_coding_transcript_exon_variant	1/4	2
ENPP1	ENST00000513998.5 link	n.73G>C		non_coding_transcript_exon_variant	1/25	5		ENSP00000422424.1	E9PE72
ENPP1	ENST00000650507.1 link	n.-15G>C		upstream_gene_variant				ENSP00000497375.1	A0A3B3IST7

Frequencies

GnomAD3 genomes

AF:

0.00000673

AC:

AN:

148590

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:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000650

AC:

AN:

1077558

Hom.:

Cov.:

AF XY:

0.00000780

AC XY:

AN XY:

512906

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000219

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000110

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000673

AC:

AN:

148590

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

72416

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:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Type 2 diabetes mellitus;C2750078:Hypophosphatemic rickets, autosomal recessive, 2;C3809781:Hypopigmentation-punctate palmoplantar keratoderma syndrome;C4054476:Inherited obesity;C4551985:Arterial calcification, generalized, of infancy, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Apr 04, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

0.0068

BayesDel_noAF

Benign

-0.23

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.26

T;T

Eigen

Uncertain

0.29

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.51

.;T

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.49

T;T

MetaSVM

Benign

-0.44

MutationAssessor

Benign

0.90

L;L

PrimateAI

Pathogenic

0.88

PROVEAN

Benign

-0.73

N;.

REVEL

Benign

0.28

Sift

Uncertain

0.0090

D;.

Sift4G

Pathogenic

0.0

D;.

Polyphen

1.0

D;D

Vest4

0.30

MutPred

0.16

Loss of MoRF binding (P = 0.0564);Loss of MoRF binding (P = 0.0564);

MVP

0.80

MPC

0.26

ClinPred

0.75

GERP RS

4.8

Varity_R

0.24

gMVP

0.26

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