rs1830971

Variant names:

• chr6-131827213-A-G
• rs1830971
• NM_006208.3:c.240+18938A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006208.3(ENPP1):​c.240+18938A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.397 in 868,464 control chromosomes in the GnomAD database, including 69,757 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.37 (10884 hom., cov: 33)
  • Exomes 𝑓: 0.40 (58873 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.482
• Publications: 4 publications found

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

ENSG00000237115 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.439 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.240+18938A>G		intron_variant	Intron 1 of 24	ENST00000647893.1	NP_006199.2
LOC100421775		n.131827213A>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.240+18938A>G		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.371 AC: 56460 AN: 151980 Hom.: 10885 Cov.: 33

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.204

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.415

Gnomad EAS AF: 0.455

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.344

Gnomad MID AF: 0.383

Gnomad NFE AF: 0.426

Gnomad OTH AF: 0.396

GnomAD4 exome AF: 0.402 AC: 288003 AN: 716366 Hom.: 58873 Cov.: 9 AF XY: 0.404 AC XY: 154988 AN XY: 383746

African (AFR) AF: 0.273 AC: 5182 AN: 19004

American (AMR) AF: 0.319 AC: 13252 AN: 41604

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 8396 AN: 20284

East Asian (EAS) AF: 0.458 AC: 16502 AN: 36030

South Asian (SAS) AF: 0.387 AC: 26664 AN: 68884

European-Finnish (FIN) AF: 0.348 AC: 17822 AN: 51170

Middle Eastern (MID) AF: 0.401 AC: 1550 AN: 3868

European-Non Finnish (NFE) AF: 0.420 AC: 184796 AN: 440286

Other (OTH) AF: 0.393 AC: 13839 AN: 35236

GnomAD4 genome AF: 0.371 AC: 56472 AN: 152098 Hom.: 10884 Cov.: 33 AF XY: 0.367 AC XY: 27271 AN XY: 74356

African (AFR) AF: 0.284 AC: 11774 AN: 41506

American (AMR) AF: 0.346 AC: 5286 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.415 AC: 1440 AN: 3472

East Asian (EAS) AF: 0.454 AC: 2346 AN: 5166

South Asian (SAS) AF: 0.389 AC: 1877 AN: 4824

European-Finnish (FIN) AF: 0.344 AC: 3634 AN: 10572

Middle Eastern (MID) AF: 0.374 AC: 110 AN: 294

European-Non Finnish (NFE) AF: 0.426 AC: 28978 AN: 67954

Other (OTH) AF: 0.398 AC: 841 AN: 2112

Alfa AF: 0.396 Hom.: 5103

Bravo AF: 0.363

Asia WGS AF: 0.425 AC: 1476 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.16
DANN	Benign	0.47
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1830971; hg19: chr6-132148353; COSMIC: COSV62937901;