rs6569759

Variant names:

• chr6-131811976-A-G
• rs6569759
• NM_006208.3:c.240+3701A>G

Your query was ambiguous. Multiple possible variants found:

• chr6-131811976-A-G
• chr6-131811976-A-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+3701A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.564 in 151,950 control chromosomes in the GnomAD database, including 25,129 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 0.56 (25129 hom., cov: 31)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.215
• Publications: 14 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=-1.02).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.240+3701A>G		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+3701A>G		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.260+3701A>G		intron_variant	Intron 1 of 3	2
ENPP1	ENST00000513998.5	n.240+3701A>G		intron_variant	Intron 1 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.153+3701A>G		intron_variant	Intron 1 of 3			ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.564 AC: 85618 AN: 151832 Hom.: 25097 Cov.: 31

Gnomad AFR AF: 0.708

Gnomad AMI AF: 0.286

Gnomad AMR AF: 0.491

Gnomad ASJ AF: 0.561

Gnomad EAS AF: 0.728

Gnomad SAS AF: 0.477

Gnomad FIN AF: 0.443

Gnomad MID AF: 0.557

Gnomad NFE AF: 0.509

Gnomad OTH AF: 0.564

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

GnomAD4 genome AF: 0.564 AC: 85704 AN: 151950 Hom.: 25129 Cov.: 31 AF XY: 0.558 AC XY: 41457 AN XY: 74252

African (AFR) AF: 0.708 AC: 29352 AN: 41454

American (AMR) AF: 0.491 AC: 7501 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.561 AC: 1945 AN: 3470

East Asian (EAS) AF: 0.728 AC: 3760 AN: 5162

South Asian (SAS) AF: 0.477 AC: 2285 AN: 4794

European-Finnish (FIN) AF: 0.443 AC: 4668 AN: 10528

Middle Eastern (MID) AF: 0.551 AC: 161 AN: 292

European-Non Finnish (NFE) AF: 0.509 AC: 34579 AN: 67946

Other (OTH) AF: 0.565 AC: 1192 AN: 2110

Alfa AF: 0.526 Hom.: 90937

Bravo AF: 0.573

Asia WGS AF: 0.585 AC: 2034 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	1.5
DANN	Benign	0.70
PhyloP100		-0.21
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: rs6569759; hg19: chr6-132133116;