6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

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

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_006208.3(ENPP1):​c.313+39_313+46dupGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0013 (1 hom., cov: 0)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.525
• 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: Uncertain_significance. The variant received 0 ACMG points.

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+46dupGTGTGTGT		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+8_313+9insGTGTGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+8_333+9insGTGTGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+8_313+9insGTGTGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.00131 AC: 180 AN: 137176 Hom.: 1 Cov.: 0

Gnomad AFR AF: 0.00325

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00151

Gnomad ASJ AF: 0.00439

Gnomad EAS AF: 0.000413

Gnomad SAS AF: 0.00141

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000298

Gnomad OTH AF: 0.00272

GnomAD4 exome AF: 0.000313 AC: 327 AN: 1044650 Hom.: 0 Cov.: 14 AF XY: 0.000323 AC XY: 171 AN XY: 529456

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000806 AC: 19 AN: 23582

American (AMR) AF: 0.000466 AC: 18 AN: 38658

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 48 AN: 20204

East Asian (EAS) AF: 0.0000840 AC: 3 AN: 35694

South Asian (SAS) AF: 0.000382 AC: 27 AN: 70708

European-Finnish (FIN) AF: 0.000177 AC: 7 AN: 39558

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

European-Non Finnish (NFE) AF: 0.000244 AC: 187 AN: 767804

Other (OTH) AF: 0.000353 AC: 16 AN: 45330

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00131 AC: 180 AN: 137264 Hom.: 1 Cov.: 0 AF XY: 0.00126 AC XY: 84 AN XY: 66772

African (AFR) AF: 0.00324 AC: 114 AN: 35212

American (AMR) AF: 0.00151 AC: 21 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.00439 AC: 13 AN: 2958

East Asian (EAS) AF: 0.000414 AC: 2 AN: 4834

South Asian (SAS) AF: 0.00141 AC: 6 AN: 4242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9364

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

European-Non Finnish (NFE) AF: 0.000298 AC: 19 AN: 63802

Other (OTH) AF: 0.00269 AC: 5 AN: 1858

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

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		-0.53
Mutation Taster		=100/0	polymorphism

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;