rs1044548

Variant names:

• chr6-131890623-G-A
• rs1044548
• NM_006208.3:c.*112G>A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006208.3(ENPP1):​c.*112G>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 0.0629 in 947,804 control chromosomes in the GnomAD database, including 3,872 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.12 (1949 hom., cov: 32)
  • Exomes 𝑓: 0.053 (1923 hom.)
• Consequence: ENPP1 NM_006208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.01

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BP6: Variant 6-131890623-G-A is Benign according to our data. Variant chr6-131890623-G-A is described in ClinVar as [Benign]. Clinvar id is 355357.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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.*112G>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.*112G>A		3_prime_UTR_variant	Exon 25 of 25		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.*1727G>A		non_coding_transcript_exon_variant	Exon 25 of 25	5		ENSP00000422424.1
ENPP1	ENST00000684674.1	n.1321G>A		non_coding_transcript_exon_variant	Exon 6 of 6
ENPP1	ENST00000513998.5	n.*1727G>A		3_prime_UTR_variant	Exon 25 of 25	5		ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17663 AN: 152092 Hom.: 1931 Cov.: 32

Gnomad AFR AF: 0.294

Gnomad AMI AF: 0.0943

Gnomad AMR AF: 0.0815

Gnomad ASJ AF: 0.0423

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0406

Gnomad FIN AF: 0.0119

Gnomad MID AF: 0.121

Gnomad NFE AF: 0.0501

Gnomad OTH AF: 0.120

GnomAD4 exome AF: 0.0527 AC: 41923 AN: 795594 Hom.: 1923 Cov.: 10 AF XY: 0.0516 AC XY: 21626 AN XY: 419290

Gnomad4 AFR exome AF: 0.296

Gnomad4 AMR exome AF: 0.0536

Gnomad4 ASJ exome AF: 0.0442

Gnomad4 EAS exome AF: 0.000144

Gnomad4 SAS exome AF: 0.0445

Gnomad4 FIN exome AF: 0.0196

Gnomad4 NFE exome AF: 0.0498

Gnomad4 OTH exome AF: 0.0691

GnomAD4 genome AF: 0.116 AC: 17718 AN: 152210 Hom.: 1949 Cov.: 32 AF XY: 0.114 AC XY: 8476 AN XY: 74430

Gnomad4 AFR AF: 0.295

Gnomad4 AMR AF: 0.0814

Gnomad4 ASJ AF: 0.0423

Gnomad4 EAS AF: 0.000578

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0119

Gnomad4 NFE AF: 0.0501

Gnomad4 OTH AF: 0.119

Alfa AF: 0.0620 Hom.: 612

Bravo AF: 0.130

Asia WGS AF: 0.0370 AC: 130 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

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	-0.72
CADD	Benign	10
DANN	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs1044548; hg19: chr6-132211763;