NM_006208.3:c.241-19616C>G

Variant names:

• chr6-131828160-C-G
• rs1409181
• NM_006208.3:c.241-19616C>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.241-19616C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.502 in 576,310 control chromosomes in the GnomAD database, including 74,322 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 0.46 (16980 hom., cov: 32)
  • Exomes 𝑓: 0.52 (57342 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0540
• Publications: 15 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=-0.9).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.241-19616C>G		intron_variant	Intron 1 of 24	ENST00000647893.1	NP_006199.2
LOC100421775		n.131828160C>G		intragenic_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.241-19616C>G		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.464 AC: 70415 AN: 151878 Hom.: 16985 Cov.: 32

Gnomad AFR AF: 0.333

Gnomad AMI AF: 0.327

Gnomad AMR AF: 0.451

Gnomad ASJ AF: 0.543

Gnomad EAS AF: 0.527

Gnomad SAS AF: 0.604

Gnomad FIN AF: 0.469

Gnomad MID AF: 0.551

Gnomad NFE AF: 0.527

Gnomad OTH AF: 0.496

GnomAD4 exome AF: 0.516 AC: 218760 AN: 424314 Hom.: 57342 Cov.: 3 AF XY: 0.526 AC XY: 125347 AN XY: 238464

African (AFR) AF: 0.334 AC: 3965 AN: 11866

American (AMR) AF: 0.392 AC: 14585 AN: 37232

Ashkenazi Jewish (ASJ) AF: 0.548 AC: 7183 AN: 13102

East Asian (EAS) AF: 0.540 AC: 9073 AN: 16804

South Asian (SAS) AF: 0.592 AC: 39157 AN: 66128

European-Finnish (FIN) AF: 0.475 AC: 14401 AN: 30298

Middle Eastern (MID) AF: 0.561 AC: 1737 AN: 3096

European-Non Finnish (NFE) AF: 0.525 AC: 118343 AN: 225512

Other (OTH) AF: 0.509 AC: 10316 AN: 20276

GnomAD4 genome AF: 0.463 AC: 70422 AN: 151996 Hom.: 16980 Cov.: 32 AF XY: 0.463 AC XY: 34395 AN XY: 74266

African (AFR) AF: 0.333 AC: 13789 AN: 41470

American (AMR) AF: 0.451 AC: 6886 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.543 AC: 1882 AN: 3464

East Asian (EAS) AF: 0.526 AC: 2715 AN: 5158

South Asian (SAS) AF: 0.603 AC: 2910 AN: 4822

European-Finnish (FIN) AF: 0.469 AC: 4947 AN: 10552

Middle Eastern (MID) AF: 0.548 AC: 161 AN: 294

European-Non Finnish (NFE) AF: 0.527 AC: 35784 AN: 67958

Other (OTH) AF: 0.498 AC: 1050 AN: 2110

Alfa AF: 0.384 Hom.: 1166

Bravo AF: 0.449

Asia WGS AF: 0.583 AC: 2026 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	4.4
DANN	Benign	0.37
PhyloP100		-0.054
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs1409181; hg19: chr6-132149300;