6-131847856-GGTGTGTGTGTGTGTGTGTGTGTGTGT-GGTGTGTGTGTGTGTGTGTGTGTGTGTGTGT

Variant names:

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

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+43_313+46dupGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.046 (184 hom., cov: 0)
  • Exomes 𝑓: 0.027 (28 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-G-GGTGT is Benign according to our data. Variant chr6-131847856-G-GGTGT is described in ClinVar as Benign. ClinVar VariationId is 773201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0574 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+43_313+46dupGTGT		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+9insGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+8_333+9insGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+8_313+9insGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0456 AC: 6249 AN: 137090 Hom.: 183 Cov.: 0

Gnomad AFR AF: 0.0137

Gnomad AMI AF: 0.152

Gnomad AMR AF: 0.0513

Gnomad ASJ AF: 0.0653

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.0635

Gnomad FIN AF: 0.0420

Gnomad MID AF: 0.0180

Gnomad NFE AF: 0.0589

Gnomad OTH AF: 0.0435

GnomAD4 exome AF: 0.0274 AC: 28449 AN: 1037612 Hom.: 28 Cov.: 14 AF XY: 0.0294 AC XY: 15447 AN XY: 525634

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

African (AFR) AF: 0.00783 AC: 184 AN: 23488

American (AMR) AF: 0.0342 AC: 1313 AN: 38344

Ashkenazi Jewish (ASJ) AF: 0.0413 AC: 822 AN: 19898

East Asian (EAS) AF: 0.0357 AC: 1265 AN: 35388

South Asian (SAS) AF: 0.0528 AC: 3699 AN: 70012

European-Finnish (FIN) AF: 0.0314 AC: 1232 AN: 39238

Middle Eastern (MID) AF: 0.0431 AC: 133 AN: 3084

European-Non Finnish (NFE) AF: 0.0241 AC: 18399 AN: 763212

Other (OTH) AF: 0.0312 AC: 1402 AN: 44948

⚠️ 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: 0.0456 AC: 6251 AN: 137178 Hom.: 184 Cov.: 0 AF XY: 0.0452 AC XY: 3013 AN XY: 66720

African (AFR) AF: 0.0136 AC: 480 AN: 35206

American (AMR) AF: 0.0513 AC: 712 AN: 13890

Ashkenazi Jewish (ASJ) AF: 0.0653 AC: 193 AN: 2956

East Asian (EAS) AF: 0.0476 AC: 230 AN: 4830

South Asian (SAS) AF: 0.0636 AC: 270 AN: 4242

European-Finnish (FIN) AF: 0.0420 AC: 392 AN: 9342

Middle Eastern (MID) AF: 0.0192 AC: 5 AN: 260

European-Non Finnish (NFE) AF: 0.0590 AC: 3761 AN: 63758

Other (OTH) AF: 0.0436 AC: 81 AN: 1856

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	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: COSV62931400;