6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGT

Variant names:

• chr6-131847856-GGTGTGT-G
• rs59956343
• NM_006208.3:c.313+41_313+46delGTGTGT

Variant summary

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

The NM_006208.3(ENPP1):​c.313+41_313+46delGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00757 in 1,180,416 control chromosomes in the GnomAD database, including 74 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.020 (64 hom., cov: 0)
  • Exomes 𝑓: 0.0060 (10 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• 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-GGTGTGT-G is Benign according to our data. Variant chr6-131847856-GGTGTGT-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 355334.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0647 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+41_313+46delGTGTGT		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+14delGTGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+9_333+14delGTGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+9_313+14delGTGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0194 AC: 2664 AN: 137130 Hom.: 64 Cov.: 0

Gnomad AFR AF: 0.0668

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00743

Gnomad ASJ AF: 0.00203

Gnomad EAS AF: 0.00145

Gnomad SAS AF: 0.00212

Gnomad FIN AF: 0.000962

Gnomad MID AF: 0.00719

Gnomad NFE AF: 0.00232

Gnomad OTH AF: 0.0196

GnomAD4 exome AF: 0.00600 AC: 6254 AN: 1043198 Hom.: 10 AF XY: 0.00558 AC XY: 2951 AN XY: 528720

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0695 AC: 1629 AN: 23438

American (AMR) AF: 0.00949 AC: 366 AN: 38578

Ashkenazi Jewish (ASJ) AF: 0.00347 AC: 70 AN: 20192

East Asian (EAS) AF: 0.00146 AC: 52 AN: 35642

South Asian (SAS) AF: 0.00360 AC: 254 AN: 70610

European-Finnish (FIN) AF: 0.00637 AC: 251 AN: 39414

Middle Eastern (MID) AF: 0.00611 AC: 19 AN: 3112

European-Non Finnish (NFE) AF: 0.00427 AC: 3274 AN: 766932

Other (OTH) AF: 0.00749 AC: 339 AN: 45280

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0195 AC: 2676 AN: 137218 Hom.: 64 Cov.: 0 AF XY: 0.0186 AC XY: 1240 AN XY: 66750

African (AFR) AF: 0.0670 AC: 2356 AN: 35174

American (AMR) AF: 0.00741 AC: 103 AN: 13892

Ashkenazi Jewish (ASJ) AF: 0.00203 AC: 6 AN: 2958

East Asian (EAS) AF: 0.00145 AC: 7 AN: 4834

South Asian (SAS) AF: 0.00212 AC: 9 AN: 4240

European-Finnish (FIN) AF: 0.000962 AC: 9 AN: 9358

Middle Eastern (MID) AF: 0.00769 AC: 2 AN: 260

European-Non Finnish (NFE) AF: 0.00232 AC: 148 AN: 63802

Other (OTH) AF: 0.0194 AC: 36 AN: 1858

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.47
Mutation Taster		=100/0	polymorphism

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;