6-131843867-A-G

Variant names:

• chr6-131843867-A-G
• rs4141767
• NM_006208.3:c.241-3909A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006208.3(ENPP1):​c.241-3909A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.178 in 149,440 control chromosomes in the GnomAD database, including 3,518 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.18 (3518 hom., cov: 31)
• Consequence: ENPP1 NM_006208.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.786
• Publications: 2 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.369 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP1	NM_006208.3	c.241-3909A>G		intron_variant	Intron 1 of 24	ENST00000647893.1	NP_006199.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENPP1	ENST00000647893.1	c.241-3909A>G		intron_variant	Intron 1 of 24		NM_006208.3	ENSP00000498074.1
ENPP1	ENST00000486853.1	n.261-3909A>G		intron_variant	Intron 1 of 3	2
ENPP1	ENST00000513998.5	n.241-3909A>G		intron_variant	Intron 1 of 24	5		ENSP00000422424.1
ENPP1	ENST00000650507.1	n.*77-3909A>G		intron_variant	Intron 2 of 3			ENSP00000497375.1

Frequencies

GnomAD3 genomes AF: 0.177 AC: 26490 AN: 149346 Hom.: 3514 Cov.: 31

Gnomad AFR AF: 0.374

Gnomad AMI AF: 0.239

Gnomad AMR AF: 0.172

Gnomad ASJ AF: 0.0933

Gnomad EAS AF: 0.0888

Gnomad SAS AF: 0.0901

Gnomad FIN AF: 0.0596

Gnomad MID AF: 0.0894

Gnomad NFE AF: 0.0938

Gnomad OTH AF: 0.166

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.178 AC: 26532 AN: 149440 Hom.: 3518 Cov.: 31 AF XY: 0.175 AC XY: 12743 AN XY: 72762

African (AFR) AF: 0.374 AC: 15258 AN: 40770

American (AMR) AF: 0.171 AC: 2580 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.0933 AC: 321 AN: 3442

East Asian (EAS) AF: 0.0886 AC: 451 AN: 5090

South Asian (SAS) AF: 0.0916 AC: 428 AN: 4670

European-Finnish (FIN) AF: 0.0596 AC: 586 AN: 9830

Middle Eastern (MID) AF: 0.0929 AC: 26 AN: 280

European-Non Finnish (NFE) AF: 0.0938 AC: 6318 AN: 67322

Other (OTH) AF: 0.167 AC: 346 AN: 2076

Alfa AF: 0.161 Hom.: 2577

Bravo AF: 0.194

Asia WGS AF: 0.0990 AC: 345 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.1
DANN	Benign	0.83
PhyloP100		-0.79
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: rs4141767; hg19: chr6-132165007;