6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr6-131847856-GGT-G
• rs59956343
• NM_006208.3:c.313+45_313+46delGT

Variant summary

Our verdict is Benign. The variant received -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
• 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: Benign. The variant received -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 VariationId is 355332.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.186 is higher than 0.05.

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+45_313+46delGT		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+9_313+10delGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+9_333+10delGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+9_313+10delGT		intron	N/A	ENSP00000422424.1

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

African (AFR) AF: 0.122 AC: 2775 AN: 22744

American (AMR) AF: 0.180 AC: 6753 AN: 37418

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 3552 AN: 19112

East Asian (EAS) AF: 0.221 AC: 7472 AN: 33884

South Asian (SAS) AF: 0.208 AC: 14182 AN: 68138

European-Finnish (FIN) AF: 0.265 AC: 10145 AN: 38354

Middle Eastern (MID) AF: 0.181 AC: 543 AN: 2996

European-Non Finnish (NFE) AF: 0.137 AC: 102840 AN: 747936

Other (OTH) AF: 0.171 AC: 7440 AN: 43616

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

African (AFR) AF: 0.107 AC: 3775 AN: 35144

American (AMR) AF: 0.141 AC: 1956 AN: 13854

Ashkenazi Jewish (ASJ) AF: 0.113 AC: 335 AN: 2958

East Asian (EAS) AF: 0.117 AC: 563 AN: 4830

South Asian (SAS) AF: 0.197 AC: 835 AN: 4232

European-Finnish (FIN) AF: 0.278 AC: 2581 AN: 9288

Middle Eastern (MID) AF: 0.181 AC: 47 AN: 260

European-Non Finnish (NFE) AF: 0.144 AC: 9173 AN: 63694

Other (OTH) AF: 0.126 AC: 234 AN: 1852

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Arterial calcification, generalized, of infancy, 1 (1)
-	-	1	Hypophosphatemic Rickets, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.53
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs59956343; hg19: chr6-132168996;