19-6307207-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_133492.3(ACER1):​c.572G>C​(p.Arg191Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,614,128 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R191C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000053 ( 0 hom., cov: 31)
Exomes 𝑓: 0.0000062 ( 0 hom. )

Consequence

ACER1
NM_133492.3 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19
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 Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
ACER1NM_133492.3 linkc.572G>C p.Arg191Pro missense_variant Exon 5 of 6 ENST00000301452.5 NP_597999.1 Q8TDN7
ACER1XM_011527673.3 linkc.443G>C p.Arg148Pro missense_variant Exon 6 of 7 XP_011525975.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
ACER1ENST00000301452.5 linkc.572G>C p.Arg191Pro missense_variant Exon 5 of 6 1 NM_133492.3 ENSP00000301452.3 Q8TDN7

Frequencies

GnomAD3 genomes
AF:
0.0000526
AC:
8
AN:
152170
Hom.:
0
Cov.:
31
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000458
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:
0.00
Gnomad OTH
AF:
0.000479
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251406
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135872
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
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:
0.00000616
AC:
9
AN:
1461840
Hom.:
0
Cov.:
32
AF XY:
0.00000275
AC XY:
2
AN XY:
727222
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000157
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:
0.00
Gnomad4 OTH exome
AF:
0.0000331
GnomAD4 genome
AF:
0.0000525
AC:
8
AN:
152288
Hom.:
0
Cov.:
31
AF XY:
0.0000403
AC XY:
3
AN XY:
74468
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000458
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000474
Bravo
AF:
0.000125
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Nov 17, 2023
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.572G>C (p.R191P) alteration is located in exon 5 (coding exon 5) of the ACER1 gene. This alteration results from a G to C substitution at nucleotide position 572, causing the arginine (R) at amino acid position 191 to be replaced by a proline (P). 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
Uncertain
0.11
D
BayesDel_noAF
Uncertain
0.010
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.58
D
Eigen
Uncertain
0.42
Eigen_PC
Uncertain
0.30
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Benign
0.83
T
M_CAP
Benign
0.079
D
MetaRNN
Pathogenic
0.79
D
MetaSVM
Benign
-0.50
T
MutationAssessor
Uncertain
2.1
M
PrimateAI
Benign
0.38
T
PROVEAN
Pathogenic
-6.0
D
REVEL
Uncertain
0.33
Sift
Uncertain
0.0020
D
Sift4G
Uncertain
0.0030
D
Polyphen
1.0
D
Vest4
0.82
MVP
0.49
MPC
1.0
ClinPred
0.99
D
GERP RS
3.4
Varity_R
0.91
gMVP
0.97

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.11
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: rs151165925; hg19: chr19-6307218; API