6-131890632-G-C

Position:

• chr6-131890632-G-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_006208.3(ENPP1):​c.*121G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.035 in 854,590 control chromosomes in the GnomAD database, including 1,548 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.072 (895 hom., cov: 32)
  • Exomes 𝑓: 0.027 (653 hom.)
• Consequence: ENPP1 NM_006208.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.42

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 6-131890632-G-C is Benign according to our data. Variant chr6-131890632-G-C is described in ClinVar as [Benign]. Clinvar id is 355358.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.204 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.*121G>C		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.*121G>C		3_prime_UTR_variant	25/25		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.*1736G>C		non_coding_transcript_exon_variant	25/25	5		ENSP00000422424.1
ENPP1	ENST00000684674.1	n.1330G>C		non_coding_transcript_exon_variant	6/6
ENPP1	ENST00000513998.5	n.*1736G>C		3_prime_UTR_variant	25/25	5		ENSP00000422424.1

Frequencies

GnomAD3 genomes AF: 0.0723 AC: 10993 AN: 152112 Hom.: 887 Cov.: 32

Gnomad AFR AF: 0.207

Gnomad AMI AF: 0.0241

Gnomad AMR AF: 0.0343

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0386

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0213

Gnomad OTH AF: 0.0621

GnomAD4 exome AF: 0.0269 AC: 18917 AN: 702360 Hom.: 653 Cov.: 9 AF XY: 0.0274 AC XY: 10230 AN XY: 373584

Gnomad4 AFR exome AF: 0.211

Gnomad4 AMR exome AF: 0.0267

Gnomad4 ASJ exome AF: 0.00918

Gnomad4 EAS exome AF: 0.000118

Gnomad4 SAS exome AF: 0.0423

Gnomad4 FIN exome AF: 0.00825

Gnomad4 NFE exome AF: 0.0210

Gnomad4 OTH exome AF: 0.0356

GnomAD4 genome AF: 0.0724 AC: 11025 AN: 152230 Hom.: 895 Cov.: 32 AF XY: 0.0711 AC XY: 5294 AN XY: 74436

Gnomad4 AFR AF: 0.207

Gnomad4 AMR AF: 0.0342

Gnomad4 ASJ AF: 0.00749

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0388

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0213

Gnomad4 OTH AF: 0.0614

Alfa AF: 0.00633 Hom.: 3

Bravo AF: 0.0803

Asia WGS AF: 0.0290 AC: 99 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

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. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 30, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	13
DANN	Benign	0.67
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: rs11964389; hg19: chr6-132211772;