NM_006208.3:c.-10C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_006208.3(ENPP1):c.-10C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.026 ( 41 hom., cov: 19)

Exomes 𝑓: 0.038 ( 247 hom. )

Consequence

ENPP1
NM_006208.3 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.907

Publications

0 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, ClinGen
hypopigmentation-punctate palmoplantar keratoderma syndrome
Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 6-131808026-C-T is Benign according to our data. Variant chr6-131808026-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 193334.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.0256 (2441/95494) while in subpopulation AMR AF = 0.0516 (338/6548). AF 95% confidence interval is 0.0471. There are 41 homozygotes in GnomAd4. There are 1147 alleles in the male GnomAd4 subpopulation. Median coverage is 19. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 41 AD,AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.-10C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	NP_006199.2	P22413
	ENPP1	NM_006208.3	MANE Select	c.-10C>T		5_prime_UTR	Exon 1 of 25	NP_006199.2	P22413

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
ENPP1	ENST00000647893.1	MANE Select	c.-10C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 25	ENSP00000498074.1	P22413
ENPP1	ENST00000647893.1	MANE Select	c.-10C>T	5_prime_UTR	Exon 1 of 25	ENSP00000498074.1	P22413
ENPP1	ENST00000922186.1		c.-10C>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 24	ENSP00000592245.1

Frequencies

GnomAD3 genomes

AF:

0.0256

AC:

2441

AN:

95458

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00624

Gnomad AMI

AF:

0.0661

Gnomad AMR

AF:

0.0517

Gnomad ASJ

AF:

0.00613

Gnomad EAS

AF:

0.000704

Gnomad SAS

AF:

0.0277

Gnomad FIN

AF:

0.0793

Gnomad MID

AF:

0.109

Gnomad NFE

AF:

0.0312

Gnomad OTH

AF:

0.0308

GnomAD2 exomes

AF:

0.500

AC:

AN:

show subpopulations

Gnomad NFE exome

AF:

0.500

GnomAD4 exome

AF:

0.0379

AC:

20094

AN:

530746

Hom.:

247

Cov.:

AF XY:

0.0379

AC XY:

9325

AN XY:

246214

show subpopulations

African (AFR)

AF:

0.00526

AC:

AN:

10270

American (AMR)

AF:

0.0295

AC:

AN:

678

Ashkenazi Jewish (ASJ)

AF:

0.00985

AC:

AN:

3248

East Asian (EAS)

AF:

0.00

AC:

AN:

2418

South Asian (SAS)

AF:

0.0224

AC:

234

AN:

10454

European-Finnish (FIN)

AF:

0.0462

AC:

AN:

238

Middle Eastern (MID)

AF:

0.0450

AC:

AN:

1022

European-Non Finnish (NFE)

AF:

0.0393

AC:

19080

AN:

485108

Other (OTH)

AF:

0.0356

AC:

617

AN:

17310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1085

2171

3256

4342

5427

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

976

1952

2928

3904

4880

<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:

0.0256

AC:

2441

AN:

95494

Hom.:

Cov.:

AF XY:

0.0263

AC XY:

1147

AN XY:

43618

show subpopulations

African (AFR)

AF:

0.00624

AC:

158

AN:

25338

American (AMR)

AF:

0.0516

AC:

338

AN:

6548

Ashkenazi Jewish (ASJ)

AF:

0.00613

AC:

AN:

2772

East Asian (EAS)

AF:

0.000704

AC:

AN:

2840

South Asian (SAS)

AF:

0.0277

AC:

AN:

2706

European-Finnish (FIN)

AF:

0.0793

AC:

149

AN:

1880

Middle Eastern (MID)

AF:

0.106

AC:

AN:

132

European-Non Finnish (NFE)

AF:

0.0312

AC:

1600

AN:

51246

Other (OTH)

AF:

0.0306

AC:

AN:

1306

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

109

219

328

438

547

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

128

160

<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:

0.0224

Hom.:

Bravo

AF:

0.0159

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

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

Hypophosphatemic rickets, autosomal recessive, 2 (1)

not provided (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

7.4

(source)

DANN

Benign

0.89

PhyloP100

-0.91

PromoterAI

0.026

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=300/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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