rs9493105

Variant names:

• chr6-131817198-C-T
• rs9493105
• NM_006208.3:c.240+8923C>T

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+8923C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0925 in 152,130 control chromosomes in the GnomAD database, including 771 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 0.092 (771 hom., cov: 32)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 6 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=-0.89).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.240+8923C>T		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.240+8923C>T		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.260+8923C>T		intron_variant	Intron 1 of 3	2
ENPP1	ENST00000513998.5	n.240+8923C>T		intron_variant	Intron 1 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.154-8824C>T		intron_variant	Intron 1 of 3			ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.0926 AC: 14073 AN: 152012 Hom.: 772 Cov.: 32

Gnomad AFR AF: 0.0455

Gnomad AMI AF: 0.121

Gnomad AMR AF: 0.104

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.0812

Gnomad SAS AF: 0.216

Gnomad FIN AF: 0.131

Gnomad MID AF: 0.168

Gnomad NFE AF: 0.101

Gnomad OTH AF: 0.108

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

GnomAD4 genome AF: 0.0925 AC: 14070 AN: 152130 Hom.: 771 Cov.: 32 AF XY: 0.0968 AC XY: 7204 AN XY: 74394

African (AFR) AF: 0.0454 AC: 1883 AN: 41448

American (AMR) AF: 0.104 AC: 1595 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 455 AN: 3472

East Asian (EAS) AF: 0.0813 AC: 422 AN: 5188

South Asian (SAS) AF: 0.215 AC: 1038 AN: 4828

European-Finnish (FIN) AF: 0.131 AC: 1391 AN: 10598

Middle Eastern (MID) AF: 0.173 AC: 51 AN: 294

European-Non Finnish (NFE) AF: 0.101 AC: 6899 AN: 67996

Other (OTH) AF: 0.107 AC: 226 AN: 2110

Alfa AF: 0.102 Hom.: 1253

Bravo AF: 0.0854

Asia WGS AF: 0.162 AC: 562 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	2.3
DANN	Benign	0.68
PhyloP100		-0.0030
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: rs9493105; hg19: chr6-132138338;