rs703184

Variant names:

• chr6-131833855-G-C
• rs703184
• NM_006208.3:c.241-13921G>C

Variant summary

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

The NM_006208.3(ENPP1):​c.241-13921G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.13 in 152,130 control chromosomes in the GnomAD database, including 1,406 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 0.13 (1406 hom., cov: 33)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.14
• Publications: 3 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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.241-13921G>C		intron_variant	Intron 1 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.241-13921G>C		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.261-13921G>C		intron_variant	Intron 1 of 3	2
ENPP1	ENST00000513998.5	n.241-13921G>C		intron_variant	Intron 1 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*76+7740G>C		intron_variant	Intron 2 of 3			ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19750 AN: 152012 Hom.: 1404 Cov.: 33

Gnomad AFR AF: 0.109

Gnomad AMI AF: 0.229

Gnomad AMR AF: 0.115

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.00944

Gnomad SAS AF: 0.157

Gnomad FIN AF: 0.228

Gnomad MID AF: 0.158

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.129

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.130 AC: 19764 AN: 152130 Hom.: 1406 Cov.: 33 AF XY: 0.135 AC XY: 10017 AN XY: 74372

African (AFR) AF: 0.109 AC: 4528 AN: 41504

American (AMR) AF: 0.115 AC: 1752 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.118 AC: 411 AN: 3470

East Asian (EAS) AF: 0.00946 AC: 49 AN: 5180

South Asian (SAS) AF: 0.157 AC: 757 AN: 4816

European-Finnish (FIN) AF: 0.228 AC: 2408 AN: 10562

Middle Eastern (MID) AF: 0.163 AC: 48 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9331 AN: 67994

Other (OTH) AF: 0.129 AC: 272 AN: 2116

Alfa AF: 0.130 Hom.: 152

Bravo AF: 0.120

Asia WGS AF: 0.0730 AC: 254 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	11
DANN	Benign	0.49
PhyloP100		3.1
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: rs703184; hg19: chr6-132154995;