rs9493120

Variant names:

• chr6-131891861-G-A
• rs9493120
• NM_006208.3:c.*1350G>A

Your query was ambiguous. Multiple possible variants found:

• chr6-131891861-G-A
• chr6-131891861-G-T

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.*1350G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.119 in 148,678 control chromosomes in the GnomAD database, including 1,959 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.12 (1959 hom., cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ENPP1 NM_006208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -3.64
• Publications: 6 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=-1.06).
• BP6: Variant 6-131891861-G-A is Benign according to our data. Variant chr6-131891861-G-A is described in ClinVar as Benign. ClinVar VariationId is 355391.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.*1350G>A		3_prime_UTR_variant	Exon 25 of 25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.*1350G>A		3_prime_UTR_variant	Exon 25 of 25		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.119 AC: 17624 AN: 148570 Hom.: 1939 Cov.: 31

Gnomad AFR AF: 0.301

Gnomad AMI AF: 0.0936

Gnomad AMR AF: 0.0849

Gnomad ASJ AF: 0.0425

Gnomad EAS AF: 0.000601

Gnomad SAS AF: 0.0404

Gnomad FIN AF: 0.0126

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.0499

Gnomad OTH AF: 0.123

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 6 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 4

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 4

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.119 AC: 17686 AN: 148678 Hom.: 1959 Cov.: 31 AF XY: 0.117 AC XY: 8463 AN XY: 72106

African (AFR) AF: 0.302 AC: 12241 AN: 40546

American (AMR) AF: 0.0848 AC: 1238 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.0425 AC: 147 AN: 3458

East Asian (EAS) AF: 0.000602 AC: 3 AN: 4980

South Asian (SAS) AF: 0.0405 AC: 191 AN: 4720

European-Finnish (FIN) AF: 0.0126 AC: 120 AN: 9534

Middle Eastern (MID) AF: 0.134 AC: 36 AN: 268

European-Non Finnish (NFE) AF: 0.0499 AC: 3373 AN: 67594

Other (OTH) AF: 0.122 AC: 252 AN: 2070

Alfa AF: 0.0707 Hom.: 406

Bravo AF: 0.130

Asia WGS AF: 0.0380 AC: 132 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Arterial calcification, generalized, of infancy, 1 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Hypophosphatemic rickets, autosomal recessive, 2 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.1
CADD	Benign	0.18
DANN	Benign	0.34
PhyloP100		-3.6
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: rs9493120; hg19: chr6-132213001;