6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr6-131847856-G-GGTGTGTGTGT
• rs59956343
• NM_006208.3:c.313+37_313+46dupGTGTGTGTGT

Variant summary

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

The NM_006208.3(ENPP1):​c.313+37_313+46dupGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000058 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• 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+37_313+46dupGTGTGTGTGT		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+9insGTGTGTGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+8_333+9insGTGTGTGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+8_313+9insGTGTGTGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0000510 AC: 7 AN: 137176 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000569

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000470

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000191 AC: 20 AN: 1044830 Hom.: 0 Cov.: 14 AF XY: 0.0000151 AC XY: 8 AN XY: 529562

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

African (AFR) AF: 0.0000424 AC: 1 AN: 23590

American (AMR) AF: 0.0000259 AC: 1 AN: 38670

Ashkenazi Jewish (ASJ) AF: 0.0000495 AC: 1 AN: 20214

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35694

South Asian (SAS) AF: 0.0000141 AC: 1 AN: 70728

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 39562

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3112

European-Non Finnish (NFE) AF: 0.0000195 AC: 15 AN: 767918

Other (OTH) AF: 0.00 AC: 0 AN: 45342

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0000000216024), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000583 AC: 8 AN: 137264 Hom.: 0 Cov.: 0 AF XY: 0.0000899 AC XY: 6 AN XY: 66774

African (AFR) AF: 0.0000568 AC: 2 AN: 35214

American (AMR) AF: 0.000144 AC: 2 AN: 13892

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 4834

South Asian (SAS) AF: 0.00 AC: 0 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: 0.0000470 AC: 3 AN: 63800

Other (OTH) AF: 0.000538 AC: 1 AN: 1858

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

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;