6-131890632-G-C

Variant names:

• chr6-131890632-G-C
• rs11964389
• NM_006208.3:c.*121G>C

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 7 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 -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 VariationId 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 rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.*121G>C		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.*121G>C		3_prime_UTR_variant	Exon 25 of 25		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000513998.5	n.*1736G>C		non_coding_transcript_exon_variant	Exon 25 of 25	5		ENSP00000422424.1
ENPP1	ENST00000684674.1	n.1330G>C		non_coding_transcript_exon_variant	Exon 6 of 6
ENPP1	ENST00000513998.5	n.*1736G>C		3_prime_UTR_variant	Exon 25 of 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

African (AFR) AF: 0.211 AC: 3747 AN: 17772

American (AMR) AF: 0.0267 AC: 981 AN: 36706

Ashkenazi Jewish (ASJ) AF: 0.00918 AC: 189 AN: 20594

East Asian (EAS) AF: 0.000118 AC: 4 AN: 33782

South Asian (SAS) AF: 0.0423 AC: 2788 AN: 65904

European-Finnish (FIN) AF: 0.00825 AC: 342 AN: 41470

Middle Eastern (MID) AF: 0.0685 AC: 190 AN: 2774

European-Non Finnish (NFE) AF: 0.0210 AC: 9425 AN: 448264

Other (OTH) AF: 0.0356 AC: 1251 AN: 35094

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

African (AFR) AF: 0.207 AC: 8604 AN: 41492

American (AMR) AF: 0.0342 AC: 524 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3472

East Asian (EAS) AF: 0.000385 AC: 2 AN: 5190

South Asian (SAS) AF: 0.0388 AC: 187 AN: 4820

European-Finnish (FIN) AF: 0.00518 AC: 55 AN: 10612

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0213 AC: 1448 AN: 68022

Other (OTH) AF: 0.0614 AC: 130 AN: 2116

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

Jan 13, 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 13, 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	-0.45
CADD	Benign	13
DANN	Benign	0.67
PhyloP100		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs11964389; hg19: chr6-132211772;