chr6-131847856-GGTGT-G

Variant names:

• chr6-131847856-GGTGT-G
• rs59956343
• NM_006208.3:c.313+43_313+46delGTGT

Variant summary

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

The ENST00000647893.1(ENPP1):​c.313+9_313+12delGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0497 in 1,171,032 control chromosomes in the GnomAD database, including 544 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.067 (356 hom., cov: 0)
  • Exomes 𝑓: 0.047 (188 hom.)
• Consequence: ENPP1 ENST00000647893.1 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 0.468
• 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-GGTGT-G is Benign according to our data. Variant chr6-131847856-GGTGT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 355333.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.117 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+43_313+46delGTGT		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+12delGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+9_333+12delGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+9_313+12delGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0669 AC: 9168 AN: 137026 Hom.: 354 Cov.: 0

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.0594

Gnomad AMR AF: 0.0643

Gnomad ASJ AF: 0.0210

Gnomad EAS AF: 0.0186

Gnomad SAS AF: 0.0123

Gnomad FIN AF: 0.0760

Gnomad MID AF: 0.0576

Gnomad NFE AF: 0.0466

Gnomad OTH AF: 0.0566

GnomAD4 exome AF: 0.0474 AC: 49042 AN: 1033918 Hom.: 188 AF XY: 0.0476 AC XY: 24946 AN XY: 523884

African (AFR) AF: 0.106 AC: 2454 AN: 23184

American (AMR) AF: 0.0777 AC: 2968 AN: 38214

Ashkenazi Jewish (ASJ) AF: 0.0304 AC: 607 AN: 19972

East Asian (EAS) AF: 0.0231 AC: 814 AN: 35200

South Asian (SAS) AF: 0.0343 AC: 2388 AN: 69676

European-Finnish (FIN) AF: 0.0959 AC: 3697 AN: 38562

Middle Eastern (MID) AF: 0.0366 AC: 112 AN: 3062

European-Non Finnish (NFE) AF: 0.0445 AC: 33841 AN: 761264

Other (OTH) AF: 0.0483 AC: 2161 AN: 44784

GnomAD4 genome AF: 0.0671 AC: 9195 AN: 137114 Hom.: 356 Cov.: 0 AF XY: 0.0665 AC XY: 4435 AN XY: 66694

African (AFR) AF: 0.120 AC: 4235 AN: 35146

American (AMR) AF: 0.0647 AC: 898 AN: 13884

Ashkenazi Jewish (ASJ) AF: 0.0210 AC: 62 AN: 2958

East Asian (EAS) AF: 0.0188 AC: 91 AN: 4832

South Asian (SAS) AF: 0.0120 AC: 51 AN: 4236

European-Finnish (FIN) AF: 0.0760 AC: 710 AN: 9336

Middle Eastern (MID) AF: 0.0654 AC: 17 AN: 260

European-Non Finnish (NFE) AF: 0.0467 AC: 2977 AN: 63764

Other (OTH) AF: 0.0560 AC: 104 AN: 1856

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
-	-	2	not provided (2)
-	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		0.47
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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;