rs7754561

Positions:

• chr6-131891554-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006208.3(ENPP1):​c.*1043A>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 0.441 in 152,028 control chromosomes in the GnomAD database, including 19,269 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.44 (19269 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 O:1
• Conservation: PhyloP100: -0.141

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.94).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.783 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.*1043A>G		3_prime_UTR_variant	25/25	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.*1043A>G		3_prime_UTR_variant	25/25		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.441 AC: 66969 AN: 151910 Hom.: 19216 Cov.: 31

Gnomad AFR AF: 0.789

Gnomad AMI AF: 0.360

Gnomad AMR AF: 0.493

Gnomad ASJ AF: 0.431

Gnomad EAS AF: 0.593

Gnomad SAS AF: 0.455

Gnomad FIN AF: 0.167

Gnomad MID AF: 0.554

Gnomad NFE AF: 0.248

Gnomad OTH AF: 0.450

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.441 AC: 67086 AN: 152028 Hom.: 19269 Cov.: 31 AF XY: 0.441 AC XY: 32788 AN XY: 74298

Gnomad4 AFR AF: 0.790

Gnomad4 AMR AF: 0.494

Gnomad4 ASJ AF: 0.431

Gnomad4 EAS AF: 0.594

Gnomad4 SAS AF: 0.454

Gnomad4 FIN AF: 0.167

Gnomad4 NFE AF: 0.248

Gnomad4 OTH AF: 0.452

Alfa AF: 0.310 Hom.: 13637

Bravo AF: 0.482

Asia WGS AF: 0.557 AC: 1936 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Hypophosphatemic rickets, autosomal recessive, 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 27, 2017

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Obesity Other:1

risk factor, no assertion criteria provided

literature only

OMIM

Feb 01, 2005

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.5
DANN	Benign	0.53

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: rs7754561; hg19: chr6-132212694; COSMIC: COSV62931179; COSMIC: COSV62931179;