6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 0P and 5B. BS1_Supporting BS2

The NM_006208.3(ENPP1):​c.313+41_313+46dupGTGTGT 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 0.011 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (2 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• 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 Likely_benign. Variant got -5 ACMG points.

• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0114 (1562/137248) while in subpopulation NFE AF= 0.0167 (1065/63794). AF 95% confidence interval is 0.0159. There are 12 homozygotes in gnomad4. There are 717 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.313+41_313+46dupGTGTGT		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+9insGTGTGT		intron_variant			NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.333+8_333+9insGTGTGT		intron_variant		2
ENPP1	ENST00000513998.5	n.313+8_313+9insGTGTGT		intron_variant		5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*149+8_*149+9insGTGTGT		intron_variant				ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1560 AN: 137160 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.0986

Gnomad AMR AF: 0.00808

Gnomad ASJ AF: 0.00710

Gnomad EAS AF: 0.00165

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.00569 AC: 5938 AN: 1042824 Hom.: 2 Cov.: 14 AF XY: 0.00593 AC XY: 3132 AN XY: 528456

Gnomad4 AFR exome AF: 0.00153

Gnomad4 AMR exome AF: 0.00547

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.000869

Gnomad4 SAS exome AF: 0.00781

Gnomad4 FIN exome AF: 0.00402

Gnomad4 NFE exome AF: 0.00595

Gnomad4 OTH exome AF: 0.00686

GnomAD4 genome AF: 0.0114 AC: 1562 AN: 137248 Hom.: 12 Cov.: 0 AF XY: 0.0107 AC XY: 717 AN XY: 66762

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.00806

Gnomad4 ASJ AF: 0.00710

Gnomad4 EAS AF: 0.00165

Gnomad4 SAS AF: 0.0153

Gnomad4 FIN AF: 0.00438

Gnomad4 NFE AF: 0.0167

Gnomad4 OTH AF: 0.0135

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 17, 2024	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -

Arterial calcification, generalized, of infancy, 1 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jun 14, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre	Dec 18, 2024	- -

Hypophosphatemic Rickets, Recessive Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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;