6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGT

Position:

• chr6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGT

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+45_313+46delGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,151,148 control chromosomes in the GnomAD database, including 1,863 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.14 (1306 hom., cov: 0)
  • Exomes 𝑓: 0.15 (557 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-GGT-G is Benign according to our data. Variant chr6-131847856-GGT-G is described in ClinVar as [Benign]. Clinvar id is 355332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr6-131847856-GGT-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 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+46delGT		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+9_313+10delGT		intron_variant			NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.333+9_333+10delGT		intron_variant		2
ENPP1	ENST00000513998.5	n.313+9_313+10delGT		intron_variant		5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*149+9_*149+10delGT		intron_variant				ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.143 AC: 19621 AN: 136864 Hom.: 1307 Cov.: 0

Gnomad AFR AF: 0.108

Gnomad AMI AF: 0.150

Gnomad AMR AF: 0.141

Gnomad ASJ AF: 0.113

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.196

Gnomad FIN AF: 0.278

Gnomad MID AF: 0.191

Gnomad NFE AF: 0.144

Gnomad OTH AF: 0.128

GnomAD4 exome AF: 0.154 AC: 155702 AN: 1014198 Hom.: 557 AF XY: 0.160 AC XY: 81912 AN XY: 513220

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.186

Gnomad4 EAS exome AF: 0.221

Gnomad4 SAS exome AF: 0.208

Gnomad4 FIN exome AF: 0.265

Gnomad4 NFE exome AF: 0.137

Gnomad4 OTH exome AF: 0.171

GnomAD4 genome AF: 0.143 AC: 19625 AN: 136950 Hom.: 1306 Cov.: 0 AF XY: 0.150 AC XY: 9982 AN XY: 66570

Gnomad4 AFR AF: 0.107

Gnomad4 AMR AF: 0.141

Gnomad4 ASJ AF: 0.113

Gnomad4 EAS AF: 0.117

Gnomad4 SAS AF: 0.197

Gnomad4 FIN AF: 0.278

Gnomad4 NFE AF: 0.144

Gnomad4 OTH AF: 0.126

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 20, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

Hypophosphatemic Rickets, Recessive Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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;