11-76861074-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1PM2PP3_Strong

The NM_018367.7(ACER3):​c.98A>G​(p.Glu33Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

ACER3
NM_018367.7 missense

Scores

12
6
1

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 5.98
Variant links:
Genes affected
ACER3 (HGNC:16066): (alkaline ceramidase 3) Enables N-acylsphingosine amidohydrolase activity and metal ion binding activity. Involved in several processes, including myelination; positive regulation of cell population proliferation; and sphingolipid metabolic process. Is integral component of Golgi membrane and integral component of endoplasmic reticulum membrane. Biomarker of hepatocellular carcinoma and non-alcoholic steatohepatitis. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity ACER3_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.99

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACER3NM_018367.7 linkc.98A>G p.Glu33Gly missense_variant Exon 1 of 11 ENST00000532485.6 NP_060837.3 Q9NUN7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACER3ENST00000532485.6 linkc.98A>G p.Glu33Gly missense_variant Exon 1 of 11 1 NM_018367.7 ENSP00000434480.1 Q9NUN7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31
Alfa
AF:
0.0000936
Hom.:
0
Bravo
AF:
0.00000756

ClinVar

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

Submissions by phenotype

Alkaline ceramidase 3 deficiency Pathogenic:1
Nov 10, 2017
OMIM
Significance: Pathogenic
Review Status: no assertion criteria provided
Collection Method: literature only

- -

not provided Uncertain:1
Dec 03, 2021
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). Experimental studies have shown that this missense change affects ACER3 function (PMID: 26792856, 30575723). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 446204). This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 33 of the ACER3 protein (p.Glu33Gly). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with childhood onset progressive leukodystrophy (PMID: 26792856). It has also been observed to segregate with disease in related individuals. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.36
D
BayesDel_noAF
Pathogenic
0.27
CADD
Pathogenic
32
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.61
D;D
Eigen
Pathogenic
0.77
Eigen_PC
Pathogenic
0.69
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.87
D;T
M_CAP
Pathogenic
0.93
D
MetaRNN
Pathogenic
0.99
D;D
MetaSVM
Uncertain
0.55
D
MutationAssessor
Pathogenic
3.7
H;.
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-6.4
D;D
REVEL
Pathogenic
0.86
Sift
Pathogenic
0.0
D;D
Sift4G
Pathogenic
0.0
D;D
Polyphen
1.0
D;P
Vest4
0.90
MutPred
0.91
Gain of catalytic residue at A32 (P = 0.0737);Gain of catalytic residue at A32 (P = 0.0737);
MVP
0.84
MPC
1.8
ClinPred
1.0
D
GERP RS
5.0
Varity_R
0.97
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.26
Details are displayed if max score is > 0.2
DS_DG_spliceai
0.26
Position offset: -12

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: rs1554988032; hg19: chr11-76572118; API