NM_006208.3:c.27C>A

Variant names:

• chr6-131808062-C-A
• rs794726927
• NM_006208.3:c.27C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_006208.3(ENPP1):​c.27C>A​(p.Gly9Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. G9G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 0)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: ENPP1 NM_006208.3 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.487
• Publications: 1 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, ClinGen
• hypopigmentation-punctate palmoplantar keratoderma syndrome

  Inheritance: AD Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP7: Synonymous conserved (PhyloP=-0.487 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006208.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	NM_006208.3	MANE Select	c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 25	NP_006199.2	P22413

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENPP1	ENST00000647893.1	MANE Select	c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 25	ENSP00000498074.1	P22413
	ENPP1	ENST00000922186.1		c.27C>A	p.Gly9Gly	synonymous	Exon 1 of 24	ENSP00000592245.1
	ENPP1	ENST00000486853.1	TSL:2	n.47C>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.0000261 AC: 1 AN: 38370 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.0000949

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000143 AC: 8 AN: 558104 Hom.: 0 Cov.: 4 AF XY: 0.0000115 AC XY: 3 AN XY: 260634

African (AFR) AF: 0.00 AC: 0 AN: 10912

American (AMR) AF: 0.00 AC: 0 AN: 1210

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3704

East Asian (EAS) AF: 0.00 AC: 0 AN: 3032

South Asian (SAS) AF: 0.00 AC: 0 AN: 10968

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1864

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1118

European-Non Finnish (NFE) AF: 0.0000158 AC: 8 AN: 506662

Other (OTH) AF: 0.00 AC: 0 AN: 18634

GnomAD4 genome AF: 0.0000261 AC: 1 AN: 38370 Hom.: 0 Cov.: 0 AF XY: 0.0000527 AC XY: 1 AN XY: 18974

African (AFR) AF: 0.0000949 AC: 1 AN: 10538

American (AMR) AF: 0.00 AC: 0 AN: 3006

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 1016

East Asian (EAS) AF: 0.00 AC: 0 AN: 1710

South Asian (SAS) AF: 0.00 AC: 0 AN: 1214

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 1580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 118

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 18372

Other (OTH) AF: 0.00 AC: 0 AN: 532

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.63
CADD	Benign	12
DANN	Benign	0.66
PhyloP100		-0.49
PromoterAI		0.25	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		3.5

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: rs794726927; hg19: chr6-132129202;