19-6309834-C-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_133492.3(ACER1):​c.351G>T​(p.Arg117Ser) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000744 in 1,613,754 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000075 ( 0 hom. )

Consequence

ACER1
NM_133492.3 missense, splice_region

Scores

7
4
8
Splicing: ADA: 0.9756
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.36
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.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.978

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACER1NM_133492.3 linkc.351G>T p.Arg117Ser missense_variant, splice_region_variant Exon 4 of 6 ENST00000301452.5 NP_597999.1 Q8TDN7
ACER1XM_011527673.3 linkc.222G>T p.Arg74Ser missense_variant, splice_region_variant Exon 5 of 7 XP_011525975.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACER1ENST00000301452.5 linkc.351G>T p.Arg117Ser missense_variant, splice_region_variant Exon 4 of 6 1 NM_133492.3 ENSP00000301452.3 Q8TDN7

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
152062
Hom.:
0
Cov.:
31
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:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
0.00000753
AC:
11
AN:
1461692
Hom.:
0
Cov.:
31
AF XY:
0.00000688
AC XY:
5
AN XY:
727138
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000989
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000658
AC:
1
AN:
152062
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
74266
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:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000113

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Mar 23, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.351G>T (p.R117S) alteration is located in exon 4 (coding exon 4) of the ACER1 gene. This alteration results from a G to T substitution at nucleotide position 351, causing the arginine (R) at amino acid position 117 to be replaced by a serine (S). 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
0.94
BayesDel_addAF
Pathogenic
0.20
D
BayesDel_noAF
Uncertain
0.050
CADD
Uncertain
25
DANN
Uncertain
0.98
DEOGEN2
Benign
0.37
T
Eigen
Benign
-0.026
Eigen_PC
Benign
-0.15
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.083
D
MetaRNN
Pathogenic
0.98
D
MetaSVM
Benign
-0.80
T
MutationAssessor
Uncertain
2.2
M
PrimateAI
Benign
0.37
T
PROVEAN
Pathogenic
-4.8
D
REVEL
Uncertain
0.29
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.75
P
Vest4
0.92
MutPred
0.88
Loss of solvent accessibility (P = 0.0606);
MVP
0.44
MPC
0.63
ClinPred
0.99
D
GERP RS
3.2
Varity_R
0.80
gMVP
0.88

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
0.98
dbscSNV1_RF
Pathogenic
0.77
SpliceAI score (max)
0.47
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.47
Position offset: 20

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: rs1269417806; hg19: chr19-6309845; API