6-131887145-G-A

Variant names:

• chr6-131887145-G-A
• rs7767111
• NM_006208.3:c.2607+421G>A

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006208.3(ENPP1):​c.2607+421G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.117 in 151,592 control chromosomes in the GnomAD database, including 1,969 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 0.12 (1969 hom., cov: 30)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.117
• Publications: 4 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=-0.97).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.292 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.2607+421G>A		intron	N/A	NP_006199.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.2607+421G>A		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000513998.5	TSL:5	n.*1444+421G>A		intron	N/A	ENSP00000422424.1
	ENPP1	ENST00000684674.1		n.1038+421G>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.117 AC: 17699 AN: 151476 Hom.: 1954 Cov.: 30

Gnomad AFR AF: 0.296

Gnomad AMI AF: 0.0945

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.0416

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0502

Gnomad OTH AF: 0.122

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

GnomAD4 genome AF: 0.117 AC: 17755 AN: 151592 Hom.: 1969 Cov.: 30 AF XY: 0.115 AC XY: 8500 AN XY: 74096

African (AFR) AF: 0.297 AC: 12253 AN: 41324

American (AMR) AF: 0.0818 AC: 1248 AN: 15260

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3466

East Asian (EAS) AF: 0.000581 AC: 3 AN: 5160

South Asian (SAS) AF: 0.0418 AC: 200 AN: 4780

European-Finnish (FIN) AF: 0.0118 AC: 123 AN: 10402

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3405 AN: 67900

Other (OTH) AF: 0.121 AC: 254 AN: 2096

Alfa AF: 0.0638 Hom.: 296

Bravo AF: 0.130

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.5
DANN	Benign	0.27
PhyloP100		0.12
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: rs7767111; hg19: chr6-132208285;