Genetic Variant ACER3:p.Leu18Pro (chr11-76861029-T-C) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_018367.7(ACER3):c.53T>C(p.Leu18Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Synonymous variant affecting the same amino acid position (i.e. L18L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACER3
NM_018367.7 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 6.62

Publications

1 publications found

Variant links:

Genes affected

ACER3 (HGNC:16066): (alkaline ceramidase 3) Enables N-acylsphingosine amidohydrolase activity and metal ion binding activity. Involved in several processes, including myelination; positive regulation of cell population proliferation; and sphingolipid metabolic process. Is integral component of Golgi membrane and integral component of endoplasmic reticulum membrane. Biomarker of hepatocellular carcinoma and non-alcoholic steatohepatitis. [provided by Alliance of Genome Resources, Apr 2022]

ACER3 Gene-Disease associations (from GenCC):

alkaline ceramidase 3 deficiency
Inheritance: Unknown, AR Classification: STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P

ACER3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.958

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018367.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACER3	NM_018367.7	MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 11	NP_060837.3
ACER3	NM_001300953.2		c.53T>C	p.Leu18Pro	missense	Exon 1 of 10	NP_001287882.1	B7Z2Q2
ACER3	NM_001300954.2		c.-304T>C		5_prime_UTR	Exon 1 of 11	NP_001287883.1	B7Z2V2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ACER3	ENST00000532485.6	TSL:1 MANE Select	c.53T>C	p.Leu18Pro	missense	Exon 1 of 11	ENSP00000434480.1	Q9NUN7-1
ACER3	ENST00000278544.9	TSL:1	n.53T>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000278544.5	J3KN85
ACER3	ENST00000525194.5	TSL:1	n.53T>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000432109.1	E9PKR3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1395888

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688578

African (AFR)

AF:

0.00

AC:

AN:

31448

American (AMR)

AF:

0.00

AC:

AN:

35668

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25126

East Asian (EAS)

AF:

0.00

AC:

AN:

35674

South Asian (SAS)

AF:

0.00

AC:

AN:

79106

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48566

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4100

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078412

Other (OTH)

AF:

0.00

AC:

AN:

57788

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Alkaline ceramidase 3 deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.39

Eigen

Uncertain

0.61

Eigen_PC

Uncertain

0.52

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.89

M_CAP

Pathogenic

0.85

MetaRNN

Pathogenic

0.96

MetaSVM

Benign

-0.45

MutationAssessor

Pathogenic

3.2

PhyloP100

6.6

PrimateAI

Pathogenic

0.89

PROVEAN

Pathogenic

-5.3

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

0.99

Vest4

0.90

MutPred

0.81

Loss of catalytic residue at L18 (P = 0.0018)

MVP

0.93

MPC

2.1

ClinPred

1.0

GERP RS

3.6

PromoterAI

0.011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.97

gMVP

0.90

Mutation Taster

=26/74

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over