19-6307235-C-T

Variant names:

• chr19-6307235-C-T
• rs147053887
• NM_133492.3:c.544G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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. 15/21 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
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.828
• Publications: 7 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId is 708470.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 21 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.544G>A	p.Val182Ile	missense	Exon 5 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.544G>A	p.Val182Ile	missense	Exon 5 of 6	ENSP00000301452.3	Q8TDN7

Frequencies

GnomAD3 genomes AF: 0.00336 AC: 511 AN: 152184 Hom.: 0 Cov.: 31

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

GnomAD2 exomes AF: 0.00370 AC: 931 AN: 251394 AF XY: 0.00380

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 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.: 21 Cov.: 32 AF XY: 0.00456 AC XY: 3315 AN XY: 727232

African (AFR) AF: 0.000568 AC: 19 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39700

South Asian (SAS) AF: 0.000556 AC: 48 AN: 86258

European-Finnish (FIN) AF: 0.0114 AC: 606 AN: 53376

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00533 AC: 5930 AN: 1112008

Other (OTH) AF: 0.00313 AC: 189 AN: 60396

GnomAD4 genome AF: 0.00336 AC: 511 AN: 152302 Hom.: 0 Cov.: 31 AF XY: 0.00332 AC XY: 247 AN XY: 74478

African (AFR) AF: 0.00106 AC: 44 AN: 41578

American (AMR) AF: 0.000785 AC: 12 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.0111 AC: 118 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00490 AC: 333 AN: 68026

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00367 Hom.: 3

Bravo AF: 0.00259

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00623 AC: 24

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.00384 AC: 33

ExAC AF: 0.00355 AC: 431

EpiCase AF: 0.00398

EpiControl AF: 0.00433

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.73	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0040
DANN	Benign	0.61
DEOGEN2	Benign	0.16	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.1
FATHMM_MKL	Benign	0.014	N
LIST_S2	Benign	0.12	T
MetaRNN	Benign	0.010	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.83
PrimateAI	Benign	0.22	T
PROVEAN	Benign	0.30	N
REVEL	Benign	0.024
Sift	Benign	0.30	T
Sift4G	Benign	0.26	T
Polyphen		0.0	B
Vest4		0.058
MVP		0.12
MPC		0.18
ClinPred		0.016	T
GERP RS		-11
Varity_R		0.024
gMVP		0.29
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs147053887; hg19: chr19-6307246; COSMIC: COSV106097660;