rs7767502

Variant names:

• chr6-131853789-G-C
• rs7767502
• NM_006208.3:c.618-1137G>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.618-1137G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 151,982 control chromosomes in the GnomAD database, including 11,982 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 0.31 (11982 hom., cov: 32)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.31
• Publications: 10 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=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.7 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.618-1137G>C		intron_variant	Intron 5 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.618-1137G>C		intron_variant	Intron 5 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.618-1137G>C		intron_variant	Intron 5 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650147.1	n.233-1137G>C		intron_variant	Intron 2 of 6			ENSP00000497519.1
ENPP1	ENST00000650437.1	n.107-1137G>C		intron_variant	Intron 1 of 13			ENSP00000497981.1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46681 AN: 151864 Hom.: 11930 Cov.: 32

Gnomad AFR AF: 0.706

Gnomad AMI AF: 0.316

Gnomad AMR AF: 0.239

Gnomad ASJ AF: 0.231

Gnomad EAS AF: 0.0933

Gnomad SAS AF: 0.145

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.142

Gnomad OTH AF: 0.281

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

GnomAD4 genome AF: 0.308 AC: 46794 AN: 151982 Hom.: 11982 Cov.: 32 AF XY: 0.302 AC XY: 22425 AN XY: 74282

African (AFR) AF: 0.707 AC: 29288 AN: 41432

American (AMR) AF: 0.238 AC: 3629 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.231 AC: 802 AN: 3468

East Asian (EAS) AF: 0.0931 AC: 482 AN: 5178

South Asian (SAS) AF: 0.146 AC: 705 AN: 4816

European-Finnish (FIN) AF: 0.123 AC: 1297 AN: 10562

Middle Eastern (MID) AF: 0.228 AC: 67 AN: 294

European-Non Finnish (NFE) AF: 0.142 AC: 9641 AN: 67978

Other (OTH) AF: 0.282 AC: 596 AN: 2114

Alfa AF: 0.231 Hom.: 955

Bravo AF: 0.334

Asia WGS AF: 0.151 AC: 529 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.030
DANN	Benign	0.41
PhyloP100		-2.3
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: rs7767502; hg19: chr6-132174929;