NM_006208.3:c.1946-387A>G

Variant names:

• chr6-131879493-A-G
• rs9493116
• NM_006208.3:c.1946-387A>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.1946-387A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.132 in 152,136 control chromosomes in the GnomAD database, including 1,995 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 (1995 hom., cov: 32)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.802
• Publications: 2 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.267 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.1946-387A>G		intron_variant	Intron 19 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.1946-387A>G		intron_variant	Intron 19 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.*783-387A>G		intron_variant	Intron 19 of 24	5		ENSP00000422424.1
ENPP1	ENST00000647981.1	n.676-387A>G		intron_variant	Intron 8 of 9
ENPP1	ENST00000684674.1	n.-11A>G		upstream_gene_variant

Frequencies

GnomAD3 genomes AF: 0.132 AC: 20085 AN: 152016 Hom.: 1989 Cov.: 32

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.235

Gnomad AMR AF: 0.131

Gnomad ASJ AF: 0.0597

Gnomad EAS AF: 0.0871

Gnomad SAS AF: 0.0887

Gnomad FIN AF: 0.0495

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0703

Gnomad OTH AF: 0.117

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

GnomAD4 genome AF: 0.132 AC: 20124 AN: 152136 Hom.: 1995 Cov.: 32 AF XY: 0.130 AC XY: 9651 AN XY: 74390

African (AFR) AF: 0.271 AC: 11252 AN: 41462

American (AMR) AF: 0.130 AC: 1993 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0597 AC: 207 AN: 3466

East Asian (EAS) AF: 0.0869 AC: 451 AN: 5188

South Asian (SAS) AF: 0.0900 AC: 434 AN: 4820

European-Finnish (FIN) AF: 0.0495 AC: 524 AN: 10596

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0703 AC: 4784 AN: 68006

Other (OTH) AF: 0.118 AC: 250 AN: 2112

Alfa AF: 0.0664 Hom.: 99

Bravo AF: 0.145

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	6.3
DANN	Benign	0.64
PhyloP100		0.80
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: rs9493116; hg19: chr6-132200633;