11-76926607-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_018367.7(ACER3):c.154G>A(p.Val52Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,598,032 control chromosomes in the GnomAD database, including 413,418 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.68 (35589 hom., cov: 32)
  • Exomes 𝑓: 0.72 (377829 hom.)
• Consequence: ACER3 NM_018367.7 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.26

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.3478816E-6).
• BP6: Variant 11-76926607-G-A is Benign according to our data. Variant chr11-76926607-G-A is described in ClinVar as [Benign]. Clinvar id is 1165287.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.734 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACER3	NM_018367.7	c.154G>A	p.Val52Ile	missense_variant	2/11	ENST00000532485.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACER3	ENST00000532485.6	c.154G>A	p.Val52Ile	missense_variant	2/11	1	NM_018367.7	P1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103348 AN: 151852 Hom.: 35557 Cov.: 32

Gnomad AFR AF: 0.633

Gnomad AMI AF: 0.789

Gnomad AMR AF: 0.549

Gnomad ASJ AF: 0.744

Gnomad EAS AF: 0.613

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.711

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.739

Gnomad OTH AF: 0.663

GnomAD3 exomes AF: 0.671 AC: 166964 AN: 248700 Hom.: 57627 AF XY: 0.678 AC XY: 91210 AN XY: 134480

Gnomad AFR exome AF: 0.635

Gnomad AMR exome AF: 0.470

Gnomad ASJ exome AF: 0.752

Gnomad EAS exome AF: 0.629

Gnomad SAS exome AF: 0.638

Gnomad FIN exome AF: 0.710

Gnomad NFE exome AF: 0.738

Gnomad OTH exome AF: 0.682

GnomAD4 exome AF: 0.719 AC: 1039821 AN: 1446060 Hom.: 377829 Cov.: 39 AF XY: 0.718 AC XY: 516996 AN XY: 719892

Gnomad4 AFR exome AF: 0.631

Gnomad4 AMR exome AF: 0.479

Gnomad4 ASJ exome AF: 0.750

Gnomad4 EAS exome AF: 0.639

Gnomad4 SAS exome AF: 0.638

Gnomad4 FIN exome AF: 0.710

Gnomad4 NFE exome AF: 0.741

Gnomad4 OTH exome AF: 0.705

GnomAD4 genome AF: 0.681 AC: 103433 AN: 151972 Hom.: 35589 Cov.: 32 AF XY: 0.673 AC XY: 49989 AN XY: 74252

Gnomad4 AFR AF: 0.634

Gnomad4 AMR AF: 0.549

Gnomad4 ASJ AF: 0.744

Gnomad4 EAS AF: 0.613

Gnomad4 SAS AF: 0.623

Gnomad4 FIN AF: 0.711

Gnomad4 NFE AF: 0.739

Gnomad4 OTH AF: 0.665

Alfa AF: 0.717 Hom.: 44543

Bravo AF: 0.670

TwinsUK AF: 0.742 AC: 2753

ALSPAC AF: 0.748 AC: 2881

ESP6500AA AF: 0.644 AC: 2835

ESP6500EA AF: 0.736 AC: 6318

ExAC AF: 0.678 AC: 82341

Asia WGS AF: 0.587 AC: 2045 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

ACER3-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 16, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.65	T
BayesDel_noAF	Benign	-0.56
Cadd	Benign	5.0
Dann	Benign	0.37
Eigen	Benign	-0.82
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.094	N
LIST_S2	Benign	0.092	T;T
MetaRNN	Benign	0.0000013	T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.42	T
PROVEAN	Benign	0.31	N;N
REVEL	Benign	0.025
Sift	Benign	1.0	T;T
Sift4G	Benign	0.59	T;T
Polyphen		0.0	.;B
Vest4		0.087
MPC		0.54
ClinPred		0.00053	T
GERP RS		2.1
Varity_R		0.055
gMVP		0.050

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

LitVar

Other links and lift over

dbSNP: rs4379869; hg19: chr11-76637651; COSMIC: COSV53599389;