6-131847856-G-GGT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BA1

The ENST00000647893.1(ENPP1):​c.313+8_313+9insGT 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 ENST00000647893.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:5
• 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 -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 VariationId is 355328.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.31 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000647893.1. 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+46dupGT		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+8_313+9insGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+8_333+9insGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+8_313+9insGT		intron	N/A	ENSP00000422424.1

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

African (AFR) AF: 0.0541 AC: 1260 AN: 23284

American (AMR) AF: 0.170 AC: 6475 AN: 38056

Ashkenazi Jewish (ASJ) AF: 0.168 AC: 3286 AN: 19596

East Asian (EAS) AF: 0.226 AC: 7939 AN: 35124

South Asian (SAS) AF: 0.154 AC: 10691 AN: 69416

European-Finnish (FIN) AF: 0.162 AC: 6289 AN: 38864

Middle Eastern (MID) AF: 0.117 AC: 356 AN: 3032

European-Non Finnish (NFE) AF: 0.102 AC: 77744 AN: 758844

Other (OTH) AF: 0.134 AC: 5968 AN: 44636

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

African (AFR) AF: 0.0963 AC: 3385 AN: 35154

American (AMR) AF: 0.262 AC: 3637 AN: 13868

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 715 AN: 2954

East Asian (EAS) AF: 0.323 AC: 1561 AN: 4826

South Asian (SAS) AF: 0.235 AC: 993 AN: 4234

European-Finnish (FIN) AF: 0.212 AC: 1976 AN: 9338

Middle Eastern (MID) AF: 0.218 AC: 57 AN: 262

European-Non Finnish (NFE) AF: 0.230 AC: 14631 AN: 63724

Other (OTH) AF: 0.215 AC: 398 AN: 1854

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	1	-	Arterial calcification, generalized, of infancy, 1 (1)
-	1	-	Hypophosphatemic Rickets, Recessive (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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

Splicing

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

Other links and lift over

dbSNP: rs59956343; hg19: chr6-132168996; COSMIC: COSV62934287;