Genetic Variant ACER3:p.Glu22* (chr11-76861040-G-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_StrongPM2

The NM_018367.7(ACER3):c.64G>T(p.Glu22*) variant causes a stop gained change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ACER3
NM_018367.7 stop_gained

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.32

Publications

0 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.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 6 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

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.64G>T	p.Glu22*	stop_gained	Exon 1 of 11	NP_060837.3
ACER3	NM_001300953.2		c.64G>T	p.Glu22*	stop_gained	Exon 1 of 10	NP_001287882.1	B7Z2Q2
ACER3	NM_001300954.2		c.-293G>T		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.64G>T	p.Glu22*	stop_gained	Exon 1 of 11	ENSP00000434480.1	Q9NUN7-1
ACER3	ENST00000278544.9	TSL:1	n.64G>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000278544.5	J3KN85
ACER3	ENST00000525194.5	TSL:1	n.64G>T		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:

1396228

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688746

African (AFR)

AF:

0.00

AC:

AN:

31480

American (AMR)

AF:

0.00

AC:

AN:

35680

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25134

East Asian (EAS)

AF:

0.00

AC:

AN:

35690

South Asian (SAS)

AF:

0.00

AC:

AN:

79100

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48704

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4122

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1078522

Other (OTH)

AF:

0.00

AC:

AN:

57796

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.91

FATHMM_MKL

Uncertain

0.93

PhyloP100

5.3

Vest4

0.22

GERP RS

4.8

PromoterAI

-0.093

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Mutation Taster

=19/181

disease causing (fs/PTC)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over