6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_006208.3(ENPP1):​c.313+43_313+46dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (184 hom., cov: 0)
  • Exomes 𝑓: 0.027 (28 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.525

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 6-131847856-G-GGTGT is Benign according to our data. Variant chr6-131847856-G-GGTGT is described in ClinVar as [Benign]. Clinvar id is 773201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0574 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.313+43_313+46dupGTGT		intron_variant		ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.313+8_313+9insGTGT		intron_variant			NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.333+8_333+9insGTGT		intron_variant		2
ENPP1	ENST00000513998.5	n.313+8_313+9insGTGT		intron_variant		5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*149+8_*149+9insGTGT		intron_variant				ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6249 AN: 137090 Hom.: 183 Cov.: 0

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0653

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.0180

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0274 AC: 28449 AN: 1037612 Hom.: 28 Cov.: 14 AF XY: 0.0294 AC XY: 15447 AN XY: 525634

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.0342

Gnomad4 ASJ exome AF: 0.0413

Gnomad4 EAS exome AF: 0.0357

Gnomad4 SAS exome AF: 0.0528

Gnomad4 FIN exome AF: 0.0314

Gnomad4 NFE exome AF: 0.0241

Gnomad4 OTH exome AF: 0.0312

GnomAD4 genome AF: 0.0456 AC: 6251 AN: 137178 Hom.: 184 Cov.: 0 AF XY: 0.0452 AC XY: 3013 AN XY: 66720

Gnomad4 AFR AF: 0.0136

Gnomad4 AMR AF: 0.0513

Gnomad4 ASJ AF: 0.0653

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.0636

Gnomad4 FIN AF: 0.0420

Gnomad4 NFE AF: 0.0590

Gnomad4 OTH AF: 0.0436

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 19, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

not specified Benign:1

Benign, no assertion criteria provided

clinical testing

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs59956343; hg19: chr6-132168996;