4-184124242-G-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_153343.4(ENPP6):c.452C>A(p.Pro151His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,580 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ENPP6 NM_153343.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.05

Genes affected

ENPP6 (HGNC:23409): (ectonucleotide pyrophosphatase/phosphodiesterase 6) Enables glycerophosphocholine cholinephosphodiesterase activity. Involved in choline metabolic process and lipid metabolic process. Located in extracellular region and plasma membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ENPP6	NM_153343.4	c.452C>A	p.Pro151His	missense_variant	3/8	ENST00000296741.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ENPP6	ENST00000296741.7	c.452C>A	p.Pro151His	missense_variant	3/8	1	NM_153343.4	P1
ENPP6	ENST00000512353.1	c.188C>A	p.Pro63His	missense_variant	4/6	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461580 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727106

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 05, 2022

The c.452C>A (p.P151H) alteration is located in exon 3 (coding exon 3) of the ENPP6 gene. This alteration results from a C to A substitution at nucleotide position 452, causing the proline (P) at amino acid position 151 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.98
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
Cadd	Pathogenic	29
Dann	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.82
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.85	D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.95	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Pathogenic	3.4	M;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-8.3	D;D
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0010	D;D
Sift4G	Uncertain	0.0070	D;.
Polyphen		1.0	D;.
Vest4		0.90
MutPred		0.78		Loss of sheet (P = 0.1158);.;
MVP		1.0
MPC		0.51
ClinPred		1.0	D
GERP RS		5.7
Varity_R		0.86
gMVP		0.94

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr4-185045395; COSMIC: COSV57072822;