NM_006208.3:c.313+41_313+46dupGTGTGT

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_006208.3(ENPP1):​c.313+41_313+46dupGTGTGT 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 0.011 (12 hom., cov: 0)
  • Exomes 𝑓: 0.0057 (2 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:3
• 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-GGTGTGT is Benign according to our data. Variant chr6-131847856-G-GGTGTGT is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 355329.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0114 (1562/137248) while in subpopulation NFE AF = 0.0167 (1065/63794). AF 95% confidence interval is 0.0159. There are 12 homozygotes in GnomAd4. There are 717 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AD,AR gene

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+46dupGTGTGT		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+9insGTGTGT		intron	N/A	ENSP00000498074.1
	ENPP1	ENST00000486853.1	TSL:2	n.333+8_333+9insGTGTGT		intron	N/A
	ENPP1	ENST00000513998.5	TSL:5	n.313+8_313+9insGTGTGT		intron	N/A	ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0114 AC: 1560 AN: 137160 Hom.: 12 Cov.: 0

Gnomad AFR AF: 0.00402

Gnomad AMI AF: 0.0986

Gnomad AMR AF: 0.00808

Gnomad ASJ AF: 0.00710

Gnomad EAS AF: 0.00165

Gnomad SAS AF: 0.0153

Gnomad FIN AF: 0.00438

Gnomad MID AF: 0.00360

Gnomad NFE AF: 0.0167

Gnomad OTH AF: 0.0125

GnomAD4 exome AF: 0.00569 AC: 5938 AN: 1042824 Hom.: 2 Cov.: 14 AF XY: 0.00593 AC XY: 3132 AN XY: 528456

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

African (AFR) AF: 0.00153 AC: 36 AN: 23550

American (AMR) AF: 0.00547 AC: 211 AN: 38606

Ashkenazi Jewish (ASJ) AF: 0.00332 AC: 67 AN: 20186

East Asian (EAS) AF: 0.000869 AC: 31 AN: 35676

South Asian (SAS) AF: 0.00781 AC: 551 AN: 70580

European-Finnish (FIN) AF: 0.00402 AC: 159 AN: 39504

Middle Eastern (MID) AF: 0.00322 AC: 10 AN: 3106

European-Non Finnish (NFE) AF: 0.00595 AC: 4563 AN: 766402

Other (OTH) AF: 0.00686 AC: 310 AN: 45214

⚠️ 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: 0.0114 AC: 1562 AN: 137248 Hom.: 12 Cov.: 0 AF XY: 0.0107 AC XY: 717 AN XY: 66762

African (AFR) AF: 0.00400 AC: 141 AN: 35212

American (AMR) AF: 0.00806 AC: 112 AN: 13890

Ashkenazi Jewish (ASJ) AF: 0.00710 AC: 21 AN: 2958

East Asian (EAS) AF: 0.00165 AC: 8 AN: 4834

South Asian (SAS) AF: 0.0153 AC: 65 AN: 4240

European-Finnish (FIN) AF: 0.00438 AC: 41 AN: 9360

Middle Eastern (MID) AF: 0.00385 AC: 1 AN: 260

European-Non Finnish (NFE) AF: 0.0167 AC: 1065 AN: 63794

Other (OTH) AF: 0.0135 AC: 25 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
-	-	3	not provided (3)
-	2	-	Arterial calcification, generalized, of infancy, 1 (2)
-	1	-	Hypophosphatemic Rickets, Recessive (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.53
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;