rs1510

chr6-131893782-C-Gchr6-131893782-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_006208.3(ENPP1):c.*3271C>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0972 in 151,750 control chromosomes in the GnomAD database, including 1,060 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.097 (1060 hom., cov: 32)
  • Exomes 𝑓: 0.50 (0 hom.)
• Consequence: ENPP1 NM_006208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 0.298

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]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 6-131893782-C-G is Benign according to our data. Variant chr6-131893782-C-G is described in ClinVar as [Benign]. Clinvar id is 355415.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.13 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP1	NM_006208.3	c.*3271C>G		3_prime_UTR_variant	25/25	ENST00000647893.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP1	ENST00000647893.1	c.*3271C>G		3_prime_UTR_variant	25/25		NM_006208.3	P1

Frequencies

GnomAD3 genomes AF: 0.0972 AC: 14745 AN: 151630 Hom.: 1062 Cov.: 32

Gnomad AFR AF: 0.0203

Gnomad AMI AF: 0.149

Gnomad AMR AF: 0.0673

Gnomad ASJ AF: 0.0898

Gnomad EAS AF: 0.00213

Gnomad SAS AF: 0.0774

Gnomad FIN AF: 0.271

Gnomad MID AF: 0.0981

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.0886

GnomAD4 exome AF: 0.500 AC: 2 AN: 4 Hom.: 0 Cov.: 0 AF XY: 0.500 AC XY: 2 AN XY: 4

Gnomad4 NFE exome AF: 0.500

GnomAD4 genome AF: 0.0972 AC: 14744 AN: 151746 Hom.: 1060 Cov.: 32 AF XY: 0.102 AC XY: 7546 AN XY: 74126

Gnomad4 AFR AF: 0.0202

Gnomad4 AMR AF: 0.0673

Gnomad4 ASJ AF: 0.0898

Gnomad4 EAS AF: 0.00233

Gnomad4 SAS AF: 0.0776

Gnomad4 FIN AF: 0.271

Gnomad4 NFE AF: 0.133

Gnomad4 OTH AF: 0.0882

Alfa AF: 0.123 Hom.: 184

Bravo AF: 0.0771

Asia WGS AF: 0.0370 AC: 128 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

Hypophosphatemic rickets, autosomal recessive, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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. -

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

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	-0.82
Cadd	Benign	2.9
Dann	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		0.95

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

Publications

LitVar

Other links and lift over

dbSNP: rs1510; hg19: chr6-132214922;