Genetic Variant ACER1:p.Val182Ile (chr19-6307235-C-T) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_133492.3(ACER1):c.544G>A(p.Val182Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00456 in 1,614,148 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0047 ( 21 hom. )

Consequence

ACER1
NM_133492.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.828

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.010295659).

BP6

Variant 19-6307235-C-T is Benign according to our data. Variant chr19-6307235-C-T is described in ClinVar as [Benign]. Clinvar id is 708470.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ACER1	NM_133492.3 link	c.544G>A	p.Val182Ile	missense_variant	Exon 5 of 6	ENST00000301452.5	NP_597999.1	Q8TDN7
ACER1	XM_011527673.3 link	c.415G>A	p.Val139Ile	missense_variant	Exon 6 of 7		XP_011525975.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ACER1	ENST00000301452.5 link	c.544G>A	p.Val182Ile	missense_variant	Exon 5 of 6	1	NM_133492.3	ENSP00000301452.3		Q8TDN7

Frequencies

GnomAD3 genomes

AF:

0.00336

AC:

511

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00106

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000786

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0111

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00489

Gnomad OTH

AF:

0.00143

GnomAD3 exomes

AF:

0.00370

AC:

931

AN:

251394

Hom.:

AF XY:

0.00380

AC XY:

517

AN XY:

135890

show subpopulations

Gnomad AFR exome

AF:

0.000923

Gnomad AMR exome

AF:

0.00116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000457

Gnomad FIN exome

AF:

0.0135

Gnomad NFE exome

AF:

0.00482

Gnomad OTH exome

AF:

0.00375

GnomAD4 exome

AF:

0.00468

AC:

6848

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00456

AC XY:

3315

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.000568

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000556

Gnomad4 FIN exome

AF:

0.0114

Gnomad4 NFE exome

AF:

0.00533

Gnomad4 OTH exome

AF:

0.00313

GnomAD4 genome

AF:

0.00336

AC:

511

AN:

152302

Hom.:

Cov.:

AF XY:

0.00332

AC XY:

247

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00106

Gnomad4 AMR

AF:

0.000785

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0111

Gnomad4 NFE

AF:

0.00490

Gnomad4 OTH

AF:

0.00142

Alfa

AF:

0.00391

Hom.:

Bravo

AF:

0.00259

TwinsUK

AF:

0.00566

AC:

ALSPAC

AF:

0.00623

AC:

ESP6500AA

AF:

0.000908

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00355

AC:

431

EpiCase

AF:

0.00398

EpiControl

AF:

0.00433

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:1

May 04, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.069

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.82

CADD

Benign

0.0040

DANN

Benign

0.61

DEOGEN2

Benign

0.16

Eigen

Benign

-1.9

Eigen_PC

Benign

-2.1

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.12

MetaRNN

Benign

0.010

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

PrimateAI

Benign

0.22

PROVEAN

Benign

0.30

REVEL

Benign

0.024

Sift

Benign

0.30

Sift4G

Benign

0.26

Polyphen

0.0

Vest4

0.058

MVP

0.12

MPC

0.18

ClinPred

0.016

GERP RS

-11

Varity_R

0.024

gMVP

0.29

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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