11-76926643-A-G

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM2 PP3 BS2

The NM_018367.7(ACER3):c.190A>G(p.Ile64Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000597 in 1,593,722 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00043 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00062 (1 hom.)
• Consequence: ACER3 NM_018367.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.693

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_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACER3	NM_018367.7	c.190A>G	p.Ile64Val	missense_variant	2/11	ENST00000532485.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACER3	ENST00000532485.6	c.190A>G	p.Ile64Val	missense_variant	2/11	1	NM_018367.7	P1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152184 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000750

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000275 AC: 69 AN: 250612 Hom.: 2 AF XY: 0.000273 AC XY: 37 AN XY: 135468

Gnomad AFR exome AF: 0.000247

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000556

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.000615 AC: 887 AN: 1441538 Hom.: 1 Cov.: 31 AF XY: 0.000596 AC XY: 428 AN XY: 718386

Gnomad4 AFR exome AF: 0.0000600

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000233

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000788

Gnomad4 OTH exome AF: 0.000335

GnomAD4 genome AF: 0.000427 AC: 65 AN: 152184 Hom.: 0 Cov.: 33 AF XY: 0.000309 AC XY: 23 AN XY: 74336

Gnomad4 AFR AF: 0.000290

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000750

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000695 Hom.: 0

Bravo AF: 0.000446

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000582 AC: 5

ExAC AF: 0.000214 AC: 26

EpiCase AF: 0.000547

EpiControl AF: 0.000653

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Apr 12, 2023

Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt ACER3 protein function. ClinVar contains an entry for this variant (Variation ID: 2052246). This variant has not been reported in the literature in individuals affected with ACER3-related conditions. This variant is present in population databases (rs142469431, gnomAD 0.05%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 64 of the ACER3 protein (p.Ile64Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.53	T
BayesDel_noAF	Benign	-0.57
Cadd	Benign	19
Dann	Benign	0.66
Eigen	Benign	-0.46
Eigen_PC	Benign	-0.24
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.69	T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.045	T;T
MetaSVM	Benign	-1.1	T
MutationTaster	Benign	1.0	D;D;N;N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.47	N;N
REVEL	Benign	0.079
Sift	Benign	0.72	T;T
Sift4G	Benign	0.51	T;T
Polyphen		0.0	.;B
Vest4		0.17
MVP		0.27
MPC		0.55
ClinPred		0.021	T
GERP RS		3.3
Varity_R		0.064
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.64		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -5

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

Publications

LitVar

Other links and lift over

dbSNP: rs142469431; hg19: chr11-76637687;