4-184116902-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_153343.4(ENPP6):​c.809G>A​(p.Arg270His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,056 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000040 ( 0 hom. )

Consequence

ENPP6
NM_153343.4 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.42
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21329668).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ENPP6NM_153343.4 linkc.809G>A p.Arg270His missense_variant Exon 5 of 8 ENST00000296741.7 NP_699174.1 Q6UWR7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ENPP6ENST00000296741.7 linkc.809G>A p.Arg270His missense_variant Exon 5 of 8 1 NM_153343.4 ENSP00000296741.2 Q6UWR7
ENPP6ENST00000512353.1 linkc.545G>A p.Arg182His missense_variant Exon 6 of 6 3 ENSP00000423497.1 D6R9P1
ENPP6ENST00000510054.1 linkn.197G>A non_coding_transcript_exon_variant Exon 2 of 3 3

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.000188
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000294
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000915
AC:
23
AN:
251470
Hom.:
0
AF XY:
0.0000809
AC XY:
11
AN XY:
135906
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000323
Gnomad NFE exome
AF:
0.000132
Gnomad OTH exome
AF:
0.000163
GnomAD4 exome
AF:
0.0000397
AC:
58
AN:
1461838
Hom.:
0
Cov.:
31
AF XY:
0.0000371
AC XY:
27
AN XY:
727218
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000262
Gnomad4 NFE exome
AF:
0.0000324
Gnomad4 OTH exome
AF:
0.000116
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152218
Hom.:
0
Cov.:
33
AF XY:
0.0000538
AC XY:
4
AN XY:
74370
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.000188
Gnomad4 NFE
AF:
0.0000294
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000397
Hom.:
0
Bravo
AF:
0.0000189
ExAC
AF:
0.0000988
AC:
12
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Apr 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.809G>A (p.R270H) 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 809, causing the arginine (R) at amino acid position 270 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
0.20
BayesDel_addAF
Benign
-0.17
T
BayesDel_noAF
Benign
-0.24
CADD
Uncertain
23
DANN
Uncertain
0.99
DEOGEN2
Benign
0.017
T;T
Eigen
Benign
-0.38
Eigen_PC
Benign
-0.39
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.93
D;D
M_CAP
Benign
0.056
D
MetaRNN
Benign
0.21
T;T
MetaSVM
Benign
-0.88
T
MutationAssessor
Benign
1.9
L;.
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-1.3
N;N
REVEL
Benign
0.27
Sift
Benign
0.12
T;D
Sift4G
Benign
0.10
T;.
Polyphen
0.80
P;.
Vest4
0.70
MVP
0.85
MPC
0.51
ClinPred
0.25
T
GERP RS
1.4
Varity_R
0.039
gMVP
0.77

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.040
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.

Other links and lift over

dbSNP: rs201276870; hg19: chr4-185038055; COSMIC: COSV57070703; API