6-131890278-A-G

Variant names:

• chr6-131890278-A-G
• rs9493119
• NM_006208.3:c.2608-63A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006208.3(ENPP1):​c.2608-63A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.061 in 1,288,838 control chromosomes in the GnomAD database, including 4,648 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1953 hom., cov: 32)
  • Exomes 𝑓: 0.054 (2695 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.47
• Publications: 5 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 6-131890278-A-G is Benign according to our data. Variant chr6-131890278-A-G is described in ClinVar as Benign. ClinVar VariationId is 1286906.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.29 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.2608-63A>G		intron_variant	Intron 24 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.2608-63A>G		intron_variant	Intron 24 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.*1445-63A>G		intron_variant	Intron 24 of 24	5		ENSP00000422424.1
ENPP1	ENST00000684674.1	n.1039-63A>G		intron_variant	Intron 5 of 5

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17672 AN: 152114 Hom.: 1935 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0819

Gnomad ASJ AF: 0.0424

Gnomad EAS AF: 0.000578

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0118

Gnomad MID AF: 0.123

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.120

GnomAD4 exome AF: 0.0536 AC: 60896 AN: 1136606 Hom.: 2695 AF XY: 0.0527 AC XY: 30629 AN XY: 581296

African (AFR) AF: 0.300 AC: 8052 AN: 26858

American (AMR) AF: 0.0530 AC: 2347 AN: 44288

Ashkenazi Jewish (ASJ) AF: 0.0438 AC: 1058 AN: 24172

East Asian (EAS) AF: 0.000157 AC: 6 AN: 38172

South Asian (SAS) AF: 0.0447 AC: 3548 AN: 79436

European-Finnish (FIN) AF: 0.0195 AC: 1035 AN: 53114

Middle Eastern (MID) AF: 0.0950 AC: 486 AN: 5114

European-Non Finnish (NFE) AF: 0.0502 AC: 40955 AN: 815952

Other (OTH) AF: 0.0689 AC: 3409 AN: 49500

GnomAD4 genome AF: 0.116 AC: 17729 AN: 152232 Hom.: 1953 Cov.: 32 AF XY: 0.114 AC XY: 8475 AN XY: 74426

African (AFR) AF: 0.295 AC: 12223 AN: 41498

American (AMR) AF: 0.0818 AC: 1250 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.0424 AC: 147 AN: 3468

East Asian (EAS) AF: 0.000579 AC: 3 AN: 5182

South Asian (SAS) AF: 0.0411 AC: 198 AN: 4820

European-Finnish (FIN) AF: 0.0118 AC: 125 AN: 10628

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.0501 AC: 3408 AN: 68028

Other (OTH) AF: 0.120 AC: 253 AN: 2114

Alfa AF: 0.0527 Hom.: 218

Bravo AF: 0.130

Asia WGS AF: 0.0390 AC: 137 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.32
DANN	Benign	0.28
PhyloP100		-2.5
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: rs9493119; hg19: chr6-132211418;