11-76860986-G-A

Position:

chr11-76860986-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_018367.7(ACER3):c.10G>A(p.Ala4Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000281 in 1,538,548 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00034 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00028 ( 1 hom. )

Consequence

ACER3
NM_018367.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.94

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.086093515).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ACER3	NM_018367.7 linkuse as main transcript	c.10G>A	p.Ala4Thr	missense_variant	1/11	ENST00000532485.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ACER3	ENST00000532485.6 linkuse as main transcript	c.10G>A	p.Ala4Thr	missense_variant	1/11	1	NM_018367.7	P1	Q9NUN7-1

Frequencies

GnomAD3 genomes

AF:

0.000335

AC:

AN:

152078

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00144

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:

0.000412

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000190

AC:

AN:

141784

Hom.:

AF XY:

0.000198

AC XY:

AN XY:

75630

show subpopulations

Gnomad AFR exome

AF:

0.000133

Gnomad AMR exome

AF:

0.000509

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:

0.000223

Gnomad OTH exome

AF:

0.000486

GnomAD4 exome

AF:

0.000276

AC:

382

AN:

1386470

Hom.:

Cov.:

AF XY:

0.000260

AC XY:

178

AN XY:

683932

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.000341

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:

0.000330

Gnomad4 OTH exome

AF:

0.000261

GnomAD4 genome

AF:

0.000335

AC:

AN:

152078

Hom.:

Cov.:

AF XY:

0.000363

AC XY:

AN XY:

74308

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00144

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000412

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000304

Hom.:

Bravo

AF:

0.000257

ExAC

AF:

0.0000812

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 04, 2022

The c.10G>A (p.A4T) alteration is located in exon 1 (coding exon 1) of the ACER3 gene. This alteration results from a G to A substitution at nucleotide position 10, causing the alanine (A) at amino acid position 4 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 17, 2023

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. An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant¬†is likely to be tolerated. This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 4 of the ACER3 protein (p.Ala4Thr). This variant is present in population databases (rs746227737, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with ACER3-related conditions. ClinVar contains an entry for this variant (Variation ID: 1478169). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.31

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.23

T;T

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.24

FATHMM_MKL

Uncertain

0.88

LIST_S2

Uncertain

0.87

D;D

M_CAP

Pathogenic

0.59

MetaRNN

Benign

0.086

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;.

MutationTaster

Benign

0.96

D;D;D;D

PrimateAI

Uncertain

0.77

PROVEAN

Benign

0.16

N;N

REVEL

Benign

0.049

Sift

Benign

0.052

T;T

Sift4G

Benign

0.28

T;T

Polyphen

0.099

B;B

Vest4

0.23

MutPred

0.23

Gain of glycosylation at A4 (P = 0.0063);Gain of glycosylation at A4 (P = 0.0063);

MVP

0.38

MPC

0.65

ClinPred

0.094

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.21

gMVP

0.27

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over