6-131847857-G-T

Variant names:

• chr6-131847857-G-T
• rs7773477
• NM_006208.3:c.313+9G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_006208.3(ENPP1):​c.313+9G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.11 (61 hom., cov: 0)
  • Exomes 𝑓: 0.082 (325 hom.)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.525
• Publications: 5 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 6-131847857-G-T is Benign according to our data. Variant chr6-131847857-G-T is described in ClinVar as [Benign]. Clinvar id is 355335.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.176 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.313+9G>T		intron_variant	Intron 2 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.313+9G>T		intron_variant	Intron 2 of 24		NM_006208.3	ENSP00000498074.1

Frequencies

GnomAD3 genomes AF: 0.109 AC: 3847 AN: 35208 Hom.: 61 Cov.: 0

Gnomad AFR AF: 0.183

Gnomad AMI AF: 0.0890

Gnomad AMR AF: 0.0606

Gnomad ASJ AF: 0.0618

Gnomad EAS AF: 0.000856

Gnomad SAS AF: 0.0806

Gnomad FIN AF: 0.181

Gnomad MID AF: 0.0375

Gnomad NFE AF: 0.0794

Gnomad OTH AF: 0.0934

GnomAD2 exomes AF: 0.0531 AC: 5932 AN: 111610 AF XY: 0.0518

Gnomad AFR exome AF: 0.141

Gnomad AMR exome AF: 0.0160

Gnomad ASJ exome AF: 0.0459

Gnomad EAS exome AF: 0.00374

Gnomad FIN exome AF: 0.0876

Gnomad NFE exome AF: 0.0567

Gnomad OTH exome AF: 0.0449

GnomAD4 exome AF: 0.0817 AC: 26789 AN: 327864 Hom.: 325 Cov.: 14 AF XY: 0.0775 AC XY: 12836 AN XY: 165614

African (AFR) AF: 0.233 AC: 1864 AN: 7996

American (AMR) AF: 0.0218 AC: 240 AN: 11022

Ashkenazi Jewish (ASJ) AF: 0.0523 AC: 384 AN: 7338

East Asian (EAS) AF: 0.000867 AC: 6 AN: 6924

South Asian (SAS) AF: 0.0582 AC: 1185 AN: 20350

European-Finnish (FIN) AF: 0.125 AC: 978 AN: 7850

Middle Eastern (MID) AF: 0.0993 AC: 107 AN: 1078

European-Non Finnish (NFE) AF: 0.0830 AC: 20913 AN: 252012

Other (OTH) AF: 0.0836 AC: 1112 AN: 13294

GnomAD4 genome AF: 0.109 AC: 3850 AN: 35196 Hom.: 61 Cov.: 0 AF XY: 0.110 AC XY: 1807 AN XY: 16456

African (AFR) AF: 0.183 AC: 1875 AN: 10246

American (AMR) AF: 0.0606 AC: 180 AN: 2968

Ashkenazi Jewish (ASJ) AF: 0.0618 AC: 54 AN: 874

East Asian (EAS) AF: 0.000861 AC: 1 AN: 1162

South Asian (SAS) AF: 0.0813 AC: 65 AN: 800

European-Finnish (FIN) AF: 0.181 AC: 266 AN: 1466

Middle Eastern (MID) AF: 0.0405 AC: 3 AN: 74

European-Non Finnish (NFE) AF: 0.0794 AC: 1345 AN: 16940

Other (OTH) AF: 0.0923 AC: 48 AN: 520

Alfa AF: 0.0555 Hom.: 327

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Sep 14, 2019

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 14, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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. -

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.75
DANN	Benign	0.44
PhyloP100		-0.53
Mutation Taster		=13/87	disease causing

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: rs7773477; hg19: chr6-132168997;