11-76861029-T-C

Position:

• chr11-76861029-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_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).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ACER3 NM_018367.7 missense
• Clinical Significance: Uncertain significance no assertion criteria provided U:1
• Conservation: PhyloP100: 6.62

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.958

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ACER3	NM_018367.7	c.53T>C	p.Leu18Pro	missense_variant	1/11	ENST00000532485.6	NP_060837.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ACER3	ENST00000532485.6	c.53T>C	p.Leu18Pro	missense_variant	1/11	1	NM_018367.7	ENSP00000434480	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1395888 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 688578

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

Submissions by phenotype

Alkaline ceramidase 3 deficiency Uncertain:1

Uncertain significance, no assertion criteria provided

research

Medical Genetics Laboratory, Tarbiat Modares University

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.39	T;T
Eigen	Uncertain	0.61
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.89	D;D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Benign	-0.45	T
MutationAssessor	Pathogenic	3.2	M;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-5.3	D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0050	D;D
Polyphen		0.99	D;D
Vest4		0.90
MutPred		0.81		Loss of catalytic residue at L18 (P = 0.0018);Loss of catalytic residue at L18 (P = 0.0018);
MVP		0.93
MPC		2.1
ClinPred		1.0	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.97
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs1944923735; hg19: chr11-76572073;