11-76926601-G-T

Variant names:

• chr11-76926601-G-T
• rs372314534
• NM_018367.7:c.148G>T

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001300954.2(ACER3):​c.-209G>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: ACER3 NM_001300954.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.49
• Publications: 1 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.897

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001300954.2. 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.148G>T	p.Gly50Cys	missense	Exon 2 of 11	NP_060837.3
	ACER3	NM_001300954.2		c.-209G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 11	NP_001287883.1	B7Z2V2
	ACER3	NM_001300955.2		c.-85G>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 10	NP_001287884.1	B7Z2V2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER3	ENST00000532485.6	TSL:1 MANE Select	c.148G>T	p.Gly50Cys	missense	Exon 2 of 11	ENSP00000434480.1	Q9NUN7-1
	ACER3	ENST00000278544.9	TSL:1	n.148G>T		non_coding_transcript_exon	Exon 2 of 11	ENSP00000278544.5	J3KN85
	ACER3	ENST00000525194.5	TSL:1	n.*29G>T		non_coding_transcript_exon	Exon 3 of 11	ENSP00000432109.1	E9PKR3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250398 AF XY: 0.00000739

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457040 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 725078

African (AFR) AF: 0.00 AC: 0 AN: 33422

American (AMR) AF: 0.00 AC: 0 AN: 44584

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39596

South Asian (SAS) AF: 0.00 AC: 0 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53382

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.03e-7 AC: 1 AN: 1107986

Other (OTH) AF: 0.00 AC: 0 AN: 60252

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.86
BayesDel_addAF	Pathogenic	0.27	D
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.78	T
M_CAP	Benign	0.038	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Benign	-0.29	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		7.5
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.3	N
REVEL	Uncertain	0.50
Sift	Uncertain	0.018	D
Sift4G	Uncertain	0.056	T
Polyphen		1.0	D
Vest4		0.95
MutPred		0.79		Gain of catalytic residue at M48 (P = 2e-04)
MVP		0.75
MPC		1.5
ClinPred		0.92	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.85
Mutation Taster		=194/106	polymorphism

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

Other links and lift over

dbSNP: rs372314534; hg19: chr11-76637645;