19-6333473-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate

The NM_133492.3(ACER1):​c.79G>A​(p.Glu27Lys) variant causes a missense change. The variant allele was found at a frequency of 0.0000874 in 1,590,872 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: 𝑓 0.000085 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000088 ( 0 hom. )

Consequence

ACER1
NM_133492.3 missense

Scores

6
11
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.94
Variant links:
Genes affected
ACER1 (HGNC:18356): (alkaline ceramidase 1) Ceramides are synthesized during epidermal differentiation and accumulate within the interstices of the stratum corneum, where they represent critical components of the epidermal permeability barrier. Excess cellular ceramide can trigger antimitogenic signals and induce apoptosis, and the ceramide metabolites sphingosine and sphingosine-1-phosphate (S1P) are important bioregulatory molecules. Ceramide hydrolysis in the nucleated cell layers regulates keratinocyte proliferation and apoptosis in response to external stress. Ceramide hydrolysis also occurs at the stratum corneum, releasing free sphingoid base that functions as an endogenous antimicrobial agent. ACER1 is highly expressed in epidermis and catalyzes the hydrolysis of very long chain ceramides to generate sphingosine (Houben et al., 2006 [PubMed 16477081]; Sun et al., 2008 [PubMed 17713573]).[supplied by OMIM, Jul 2010]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM1
In a binding_site (size 0) in uniprot entity ACER1_HUMAN
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.902

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACER1NM_133492.3 linkc.79G>A p.Glu27Lys missense_variant Exon 1 of 6 ENST00000301452.5 NP_597999.1 Q8TDN7
ACER1XM_011527673.3 linkc.-37+19883G>A intron_variant Intron 2 of 6 XP_011525975.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACER1ENST00000301452.5 linkc.79G>A p.Glu27Lys missense_variant Exon 1 of 6 1 NM_133492.3 ENSP00000301452.3 Q8TDN7

Frequencies

GnomAD3 genomes
AF:
0.0000854
AC:
13
AN:
152190
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000483
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00145
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00316
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000163
AC:
35
AN:
214186
Hom.:
0
AF XY:
0.000243
AC XY:
28
AN XY:
115386
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:
0.00124
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000107
Gnomad OTH exome
AF:
0.000183
GnomAD4 exome
AF:
0.0000876
AC:
126
AN:
1438564
Hom.:
0
Cov.:
31
AF XY:
0.000136
AC XY:
97
AN XY:
713382
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00136
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000727
Gnomad4 OTH exome
AF:
0.0000840
GnomAD4 genome
AF:
0.0000854
AC:
13
AN:
152308
Hom.:
0
Cov.:
32
AF XY:
0.0000806
AC XY:
6
AN XY:
74472
show subpopulations
Gnomad4 AFR
AF:
0.0000481
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00145
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000680
Hom.:
0
Bravo
AF:
0.0000264
ExAC
AF:
0.000141
AC:
17
Asia WGS
AF:
0.00173
AC:
6
AN:
3478

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Feb 21, 2025
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.79G>A (p.E27K) alteration is located in exon 1 (coding exon 1) of the ACER1 gene. This alteration results from a G to A substitution at nucleotide position 79, causing the glutamic acid (E) at amino acid position 27 to be replaced by a lysine (K). 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
0.96
BayesDel_addAF
Uncertain
0.039
T
BayesDel_noAF
Pathogenic
0.24
CADD
Pathogenic
31
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.59
D
Eigen
Uncertain
0.60
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Uncertain
0.86
D
M_CAP
Uncertain
0.096
D
MetaRNN
Pathogenic
0.90
D
MetaSVM
Uncertain
0.21
D
MutationAssessor
Benign
1.9
L
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.5
D
REVEL
Pathogenic
0.70
Sift
Pathogenic
0.0
D
Sift4G
Uncertain
0.0070
D
Polyphen
0.99
D
Vest4
0.97
MutPred
0.88
Gain of methylation at E27 (P = 0.0039);
MVP
0.72
MPC
0.89
ClinPred
0.26
T
GERP RS
4.9
Varity_R
0.81
gMVP
0.98

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.

Other links and lift over

dbSNP: rs771355747; hg19: chr19-6333484; API