NM_006208.3:c.313+39_313+46delGTGTGTGT

Variant names:

• chr6-131847856-GGTGTGTGT-G
• rs59956343
• NM_006208.3:c.313+39_313+46delGTGTGTGT

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP6_Moderate BS1

The NM_006208.3(ENPP1):​c.313+39_313+46delGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000459 in 1,181,894 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00044 (0 hom., cov: 0)
  • Exomes 𝑓: 0.00046 (0 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.721
• 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: Likely_benign. The variant received -6 ACMG points.

• BP6: Variant 6-131847856-GGTGTGTGT-G is Benign according to our data. Variant chr6-131847856-GGTGTGTGT-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1114458.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.000461 (482/1044632) while in subpopulation AFR AF = 0.0048 (113/23552). AF 95% confidence interval is 0.00408. There are 0 homozygotes in GnomAdExome4. There are 208 alleles in the male GnomAdExome4 subpopulation. This position passed quality control check.

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.313+39_313+46delGTGTGTGT		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.313+9_313+16delGTGTGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+9_333+16delGTGTGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+9_313+16delGTGTGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.000430 AC: 59 AN: 137174 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.00108

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000216

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000619

Gnomad SAS AF: 0.000471

Gnomad FIN AF: 0.000107

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000188

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000461 AC: 482 AN: 1044632 Hom.: 0 AF XY: 0.000393 AC XY: 208 AN XY: 529460

African (AFR) AF: 0.00480 AC: 113 AN: 23552

American (AMR) AF: 0.000336 AC: 13 AN: 38666

Ashkenazi Jewish (ASJ) AF: 0.0000989 AC: 2 AN: 20216

East Asian (EAS) AF: 0.000280 AC: 10 AN: 35694

South Asian (SAS) AF: 0.000255 AC: 18 AN: 70716

European-Finnish (FIN) AF: 0.000101 AC: 4 AN: 39540

Middle Eastern (MID) AF: 0.000643 AC: 2 AN: 3112

European-Non Finnish (NFE) AF: 0.000386 AC: 296 AN: 767808

Other (OTH) AF: 0.000529 AC: 24 AN: 45328

GnomAD4 genome AF: 0.000437 AC: 60 AN: 137262 Hom.: 0 Cov.: 0 AF XY: 0.000464 AC XY: 31 AN XY: 66774

African (AFR) AF: 0.00111 AC: 39 AN: 35212

American (AMR) AF: 0.000216 AC: 3 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2958

East Asian (EAS) AF: 0.000621 AC: 3 AN: 4834

South Asian (SAS) AF: 0.000471 AC: 2 AN: 4242

European-Finnish (FIN) AF: 0.000107 AC: 1 AN: 9362

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 260

European-Non Finnish (NFE) AF: 0.000188 AC: 12 AN: 63802

Other (OTH) AF: 0.00 AC: 0 AN: 1858

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.72

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs59956343; hg19: chr6-132168996;