6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BA1

The NM_006208.3(ENPP1):​c.313+45_313+46dupGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.20 (2793 hom., cov: 0)
  • Exomes 𝑓: 0.12 (194 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• 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 -9 ACMG points.

• BP6: Variant 6-131847856-G-GGT is Benign according to our data. Variant chr6-131847856-G-GGT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 355328.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=3}.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.313+45_313+46dupGT		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+9insGT		intron_variant			NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.333+8_333+9insGT		intron_variant		2
ENPP1	ENST00000513998.5	n.313+8_313+9insGT		intron_variant		5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*149+8_*149+9insGT		intron_variant				ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.201 AC: 27476 AN: 136968 Hom.: 2795 Cov.: 0

Gnomad AFR AF: 0.0964

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.262

Gnomad ASJ AF: 0.242

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.234

Gnomad FIN AF: 0.212

Gnomad MID AF: 0.211

Gnomad NFE AF: 0.230

Gnomad OTH AF: 0.214

GnomAD4 exome AF: 0.116 AC: 120008 AN: 1030852 Hom.: 194 Cov.: 14 AF XY: 0.122 AC XY: 63581 AN XY: 522134

Gnomad4 AFR exome AF: 0.0541

Gnomad4 AMR exome AF: 0.170

Gnomad4 ASJ exome AF: 0.168

Gnomad4 EAS exome AF: 0.226

Gnomad4 SAS exome AF: 0.154

Gnomad4 FIN exome AF: 0.162

Gnomad4 NFE exome AF: 0.102

Gnomad4 OTH exome AF: 0.134

GnomAD4 genome AF: 0.200 AC: 27479 AN: 137056 Hom.: 2793 Cov.: 0 AF XY: 0.204 AC XY: 13633 AN XY: 66670

Gnomad4 AFR AF: 0.0963

Gnomad4 AMR AF: 0.262

Gnomad4 ASJ AF: 0.242

Gnomad4 EAS AF: 0.323

Gnomad4 SAS AF: 0.235

Gnomad4 FIN AF: 0.212

Gnomad4 NFE AF: 0.230

Gnomad4 OTH AF: 0.215

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:5

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 09, 2019	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 24, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Hypophosphatemic Rickets, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Arterial calcification, generalized, of infancy, 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Jul 19, 2020

- -

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;