rs76925618

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_StrongBS2

The NM_133492.3(ACER1):c.663G>A(p.Met221Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00687 in 1,614,050 control chromosomes in the GnomAD database, including 49 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M221V) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0057 ( 6 hom., cov: 32)

Exomes 𝑓: 0.0070 ( 43 hom. )

Consequence

ACER1
NM_133492.3 missense

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: -0.643

Publications

6 publications found

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 was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP6

Variant 19-6306846-C-T is Benign according to our data. Variant chr19-6306846-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 778808.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS2

High Homozygotes in GnomAd4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_133492.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER1	NM_133492.3	MANE Select	c.663G>A	p.Met221Ile	missense	Exon 6 of 6	NP_597999.1	Q8TDN7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER1	ENST00000301452.5	TSL:1 MANE Select	c.663G>A	p.Met221Ile	missense	Exon 6 of 6	ENSP00000301452.3	Q8TDN7

Frequencies

GnomAD3 genomes

AF:

0.00576

AC:

876

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00162

Gnomad AMI

AF:

0.0406

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00691

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00248

Gnomad FIN

AF:

0.00480

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.00872

Gnomad OTH

AF:

0.00621

GnomAD2 exomes

AF:

0.00530

AC:

1329

AN:

250980

AF XY:

0.00545

show subpopulations

Gnomad AFR exome

AF:

0.00154

Gnomad AMR exome

AF:

0.00324

Gnomad ASJ exome

AF:

0.00488

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.00487

Gnomad NFE exome

AF:

0.00814

Gnomad OTH exome

AF:

0.00572

GnomAD4 exome

AF:

0.00698

AC:

10209

AN:

1461740

Hom.:

Cov.:

AF XY:

0.00700

AC XY:

5091

AN XY:

727172

show subpopulations

African (AFR)

AF:

0.00170

AC:

AN:

33480

American (AMR)

AF:

0.00421

AC:

188

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00498

AC:

130

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39700

South Asian (SAS)

AF:

0.00263

AC:

227

AN:

86244

European-Finnish (FIN)

AF:

0.00461

AC:

246

AN:

53418

Middle Eastern (MID)

AF:

0.0172

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.00798

AC:

8868

AN:

1111920

Other (OTH)

AF:

0.00649

AC:

392

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.478

Heterozygous variant carriers

566

1131

1697

2262

2828

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

318

636

954

1272

1590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00574

AC:

874

AN:

152310

Hom.:

Cov.:

AF XY:

0.00556

AC XY:

414

AN XY:

74474

show subpopulations

African (AFR)

AF:

0.00161

AC:

AN:

41572

American (AMR)

AF:

0.00451

AC:

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.00691

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00249

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00480

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00872

AC:

593

AN:

68024

Other (OTH)

AF:

0.00662

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

136

181

226

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00715

Hom.:

Bravo

AF:

0.00566

TwinsUK

AF:

0.00620

AC:

ALSPAC

AF:

0.00597

AC:

ESP6500AA

AF:

0.00113

AC:

ESP6500EA

AF:

0.00860

AC:

ExAC

AF:

0.00498

AC:

604

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00949

EpiControl

AF:

0.00996

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.69

CADD

Benign

0.49

(source)

DANN

Benign

0.73

DEOGEN2

Benign

0.15

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.57

M_CAP

Benign

0.0053

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.76

PhyloP100

-0.64

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.30

REVEL

Benign

0.079

Sift

Benign

0.36

Sift4G

Benign

0.59

Polyphen

0.0

Vest4

0.082

MutPred

0.45

Gain of sheet (P = 0.039)

MVP

0.085

MPC

0.25

ClinPred

0.0032

GERP RS

-4.3

Varity_R

0.044

gMVP

0.36

Mutation Taster

=97/3

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.41

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.41

Position offset: -2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over