Genetic Variant ACER1:p.Arg245Gln (chr19-6306775-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

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

The NM_133492.3(ACER1):c.734G>A(p.Arg245Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000144 in 1,461,852 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

ACER1
NM_133492.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.914

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]

ACER1 links:

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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=0.09210676).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACER1	NM_133492.3 link	c.734G>A	p.Arg245Gln	missense_variant	Exon 6 of 6	ENST00000301452.5	NP_597999.1	Q8TDN7
ACER1	XM_011527673.3 link	c.605G>A	p.Arg202Gln	missense_variant	Exon 7 of 7		XP_011525975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACER1	ENST00000301452.5 link	c.734G>A	p.Arg245Gln	missense_variant	Exon 6 of 6	1	NM_133492.3	ENSP00000301452.3		Q8TDN7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000677

AC:

AN:

250930

Hom.:

AF XY:

0.0000590

AC XY:

AN XY:

135672

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

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:

0.0000144

AC:

AN:

1461852

Hom.:

Cov.:

AF XY:

0.0000138

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000358

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000416

ExAC

AF:

0.0000741

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 30, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.734G>A (p.R245Q) alteration is located in exon 6 (coding exon 6) of the ACER1 gene. This alteration results from a G to A substitution at nucleotide position 734, causing the arginine (R) at amino acid position 245 to be replaced by a glutamine (Q). 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

0.073

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.56

CADD

Benign

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.18

Eigen

Benign

0.12

Eigen_PC

Benign

0.14

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.69

M_CAP

Benign

0.014

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.1

REVEL

Benign

0.11

Sift

Benign

0.33

Sift4G

Benign

0.49

Polyphen

0.85

Vest4

0.057

MutPred

0.51

Loss of sheet (P = 0.0817);

MVP

0.39

MPC

0.33

ClinPred

0.11

GERP RS

3.4

Varity_R

0.040

gMVP

0.36

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over