11-76861040-G-C

Variant names:

• chr11-76861040-G-C
• rs1205424696
• NM_018367.7:c.64G>C

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_018367.7(ACER3):​c.64G>C​(p.Glu22Gln) variant causes a missense change. The variant allele was found at a frequency of 0.000000716 in 1,396,228 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E22K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ACER3 NM_018367.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.32
• Publications: 0 publications found

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

ACMG classification

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, 0.977

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER3	NM_018367.7	MANE Select	c.64G>C	p.Glu22Gln	missense	Exon 1 of 11	NP_060837.3
	ACER3	NM_001300953.2		c.64G>C	p.Glu22Gln	missense	Exon 1 of 10	NP_001287882.1	B7Z2Q2
	ACER3	NM_001300954.2		c.-293G>C		5_prime_UTR	Exon 1 of 11	NP_001287883.1	B7Z2V2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER3	ENST00000532485.6	TSL:1 MANE Select	c.64G>C	p.Glu22Gln	missense	Exon 1 of 11	ENSP00000434480.1	Q9NUN7-1
	ACER3	ENST00000278544.9	TSL:1	n.64G>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000278544.5	J3KN85
	ACER3	ENST00000525194.5	TSL:1	n.64G>C		non_coding_transcript_exon	Exon 1 of 11	ENSP00000432109.1	E9PKR3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 7.16e-7 AC: 1 AN: 1396228 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688746

African (AFR) AF: 0.00 AC: 0 AN: 31480

American (AMR) AF: 0.00 AC: 0 AN: 35680

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25134

East Asian (EAS) AF: 0.00 AC: 0 AN: 35690

South Asian (SAS) AF: 0.00 AC: 0 AN: 79100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48704

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4122

European-Non Finnish (NFE) AF: 9.27e-7 AC: 1 AN: 1078522

Other (OTH) AF: 0.00 AC: 0 AN: 57796

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.69
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.92	D
M_CAP	Pathogenic	0.79	D
MetaRNN	Pathogenic	0.98	D
MetaSVM	Uncertain	0.43	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		5.3
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.7	D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.056	T
Polyphen		0.94	P
Vest4		0.54
MutPred		0.95		Gain of catalytic residue at E22 (P = 0.1152)
MVP		0.83
MPC		1.5
ClinPred		1.0	D
GERP RS		4.8
PromoterAI		0.024	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6
Varity_R		0.97
gMVP		0.90
Mutation Taster		=28/72	disease causing

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: rs1205424696; hg19: chr11-76572084;