NM_006208.3:c.517A>C

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BA1

The NM_006208.3(ENPP1):c.517A>C(p.Lys173Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.177 in 1,613,790 control chromosomes in the GnomAD database, including 41,008 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.33 ( 14194 hom., cov: 32)

Exomes 𝑓: 0.16 ( 26814 hom. )

Consequence

ENPP1
NM_006208.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:10O:3

Conservation

PhyloP100: 1.45

Publications

285 publications found

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 Gene-Disease associations (from GenCC):

arterial calcification, generalized, of infancy, 1
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
hypopigmentation-punctate palmoplantar keratoderma syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Genomics England PanelApp, Orphanet, G2P, Labcorp Genetics (formerly Invitae)
hypophosphatemic rickets, autosomal recessive, 2
Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
arterial calcification of infancy
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive hypophosphatemic rickets
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
autosomal recessive inherited pseudoxanthoma elasticum
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENPP1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 4 uncertain in NM_006208.3

BP4

Computational evidence support a benign effect (MetaRNN=9.3244637E-7).

BP6

Variant 6-131851228-A-C is Benign according to our data. Variant chr6-131851228-A-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 13589.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.768 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.517A>C	p.Lys173Gln	missense	Exon 4 of 25	NP_006199.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
ENPP1	ENST00000647893.1	MANE Select	c.517A>C	p.Lys173Gln	missense	Exon 4 of 25	ENSP00000498074.1
ENPP1	ENST00000922186.1		c.517A>C	p.Lys173Gln	missense	Exon 4 of 24	ENSP00000592245.1
ENPP1	ENST00000486853.1	TSL:2	n.537A>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes

AF:

0.328

AC:

49878

AN:

152022

Hom.:

14135

Cov.:

show subpopulations

Gnomad AFR

AF:

0.775

Gnomad AMI

AF:

0.316

Gnomad AMR

AF:

0.245

Gnomad ASJ

AF:

0.232

Gnomad EAS

AF:

0.0944

Gnomad SAS

AF:

0.176

Gnomad FIN

AF:

0.122

Gnomad MID

AF:

0.234

Gnomad NFE

AF:

0.142

Gnomad OTH

AF:

0.295

GnomAD2 exomes

AF:

0.195

AC:

48946

AN:

251206

AF XY:

0.183

show subpopulations

Gnomad AFR exome

AF:

0.786

Gnomad AMR exome

AF:

0.188

Gnomad ASJ exome

AF:

0.219

Gnomad EAS exome

AF:

0.0977

Gnomad FIN exome

AF:

0.128

Gnomad NFE exome

AF:

0.146

Gnomad OTH exome

AF:

0.181

GnomAD4 exome

AF:

0.162

AC:

236113

AN:

1461650

Hom.:

26814

Cov.:

AF XY:

0.159

AC XY:

115934

AN XY:

727146

show subpopulations

African (AFR)

AF:

0.798

AC:

26703

AN:

33472

American (AMR)

AF:

0.193

AC:

8616

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.222

AC:

5790

AN:

26130

East Asian (EAS)

AF:

0.0933

AC:

3702

AN:

39698

South Asian (SAS)

AF:

0.171

AC:

14748

AN:

86258

European-Finnish (FIN)

AF:

0.128

AC:

6835

AN:

53418

Middle Eastern (MID)

AF:

0.230

AC:

1326

AN:

5760

European-Non Finnish (NFE)

AF:

0.141

AC:

156371

AN:

1111812

Other (OTH)

AF:

0.199

AC:

12022

AN:

60384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

10393

20787

31180

41574

51967

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

5926

11852

17778

23704

29630

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.329

AC:

49999

AN:

152140

Hom.:

14194

Cov.:

AF XY:

0.322

AC XY:

23968

AN XY:

74384

show subpopulations

African (AFR)

AF:

0.776

AC:

32172

AN:

41482

American (AMR)

AF:

0.245

AC:

3742

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.232

AC:

806

AN:

3470

East Asian (EAS)

AF:

0.0942

AC:

486

AN:

5160

South Asian (SAS)

AF:

0.177

AC:

857

AN:

4830

European-Finnish (FIN)

AF:

0.122

AC:

1288

AN:

10582

Middle Eastern (MID)

AF:

0.235

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.142

AC:

9668

AN:

68002

Other (OTH)

AF:

0.296

AC:

623

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1129

2259

3388

4518

5647

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

398

796

1194

1592

1990

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.214

Hom.:

16963

Bravo

AF:

0.356

TwinsUK

AF:

0.143

AC:

530

ALSPAC

AF:

0.141

AC:

543

ESP6500AA

AF:

0.751

AC:

3310

ESP6500EA

AF:

0.145

AC:

1245

ExAC

AF:

0.206

AC:

25043

Asia WGS

AF:

0.163

AC:

570

AN:

3478

EpiCase

AF:

0.151

EpiControl

AF:

0.150

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Arterial calcification, generalized, of infancy, 1 (2)

Hypophosphatemic rickets, autosomal recessive, 2 (2)

ENPP1-related disorder (1)

Hypophosphatemic rickets (1)

Hypopigmentation-punctate palmoplantar keratoderma syndrome (1)

not provided (1)

not specified (1)

Type 2 diabetes mellitus (1)

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 (1)

Diabetes mellitus type 2, susceptibility to (1)

Insulin resistance, susceptibility to (1)

Obesity (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.40

Eigen

Benign

-0.74

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.37

MetaRNN

Benign

9.3e-7

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

PhyloP100

1.4

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.6

REVEL

Benign

0.055

Sift

Benign

0.32

Sift4G

Benign

0.38

Polyphen

0.072

Vest4

0.031

MPC

0.22

ClinPred

0.016

GERP RS

3.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.086

gMVP

0.59

Mutation Taster

=99/1

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over