Genetic Variant ENPP6:p.Arg232His (chr4-184117016-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_153343.4(ENPP6):c.695G>A(p.Arg232His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000039 in 1,614,166 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R232C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

ENPP6
NM_153343.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.15

Variant links:

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]

ENPP6 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054668993).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ENPP6	NM_153343.4 link	c.695G>A	p.Arg232His	missense_variant	Exon 5 of 8	ENST00000296741.7	NP_699174.1	Q6UWR7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ENPP6	ENST00000296741.7 link	c.695G>A	p.Arg232His	missense_variant	Exon 5 of 8	1	NM_153343.4	ENSP00000296741.2	Q6UWR7
ENPP6	ENST00000512353.1 link	c.431G>A	p.Arg144His	missense_variant	Exon 6 of 6	3		ENSP00000423497.1	D6R9P1
ENPP6	ENST00000510054.1 link	n.83G>A		non_coding_transcript_exon_variant	Exon 2 of 3	3

Frequencies

GnomAD3 genomes

AF:

0.000197

AC:

AN:

152172

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000627

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

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:

0.0000294

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251434

Hom.:

AF XY:

0.0000515

AC XY:

AN XY:

135894

show subpopulations

Gnomad AFR exome

AF:

0.000738

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1461876

Hom.:

Cov.:

AF XY:

0.0000206

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.0000447

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000989

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.000197

AC:

AN:

152290

Hom.:

Cov.:

AF XY:

0.000201

AC XY:

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.000626

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000270

Hom.:

Bravo

AF:

0.000174

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000906

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 12, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.695G>A (p.R232H) alteration is located in exon 5 (coding exon 5) of the ENPP6 gene. This alteration results from a G to A substitution at nucleotide position 695, causing the arginine (R) at amino acid position 232 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

Benign

0.079

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Benign

0.92

DEOGEN2

Benign

0.033

T;T

Eigen

Benign

-0.98

Eigen_PC

Benign

-0.93

FATHMM_MKL

Benign

0.0093

LIST_S2

Benign

0.52

T;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.055

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.59

N;.

PrimateAI

Benign

0.26

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.15

Sift

Benign

0.21

T;T

Sift4G

Benign

0.13

T;.

Polyphen

0.0

B;.

Vest4

0.070

MVP

0.75

MPC

0.11

ClinPred

0.013

GERP RS

0.0044

Varity_R

0.035

gMVP

0.40

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over