11-76861021-C-T

Variant names:

• chr11-76861021-C-T
• rs138662843
• NM_018367.7:c.45C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Moderate BP6_Moderate BP7 BS2

The NM_018367.7(ACER3):​c.45C>T​(p.Thr15Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000257 in 1,547,696 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Synonymous variant affecting the same amino acid position (i.e. T15T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0013 (2 hom., cov: 31)
  • Exomes 𝑓: 0.00014 (1 hom.)
• Consequence: ACER3 NM_018367.7 synonymous
• Clinical Significance: Benign criteria provided, single submitter B:2
• Conservation: PhyloP100: 1.24
• Publications: 0 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.34).
• BP6: Variant 11-76861021-C-T is Benign according to our data. Variant chr11-76861021-C-T is described in ClinVar as Benign. ClinVar VariationId is 1653177.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=1.24 with no splicing effect.
• BS2: High Homozygotes in GnomAd4 at 2 Unknown,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_018367.7. 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.45C>T	p.Thr15Thr	synonymous	Exon 1 of 11	NP_060837.3
	ACER3	NM_001300953.2		c.45C>T	p.Thr15Thr	synonymous	Exon 1 of 10	NP_001287882.1	B7Z2Q2
	ACER3	NM_001300954.2		c.-312C>T		5_prime_UTR	Exon 1 of 11	NP_001287883.1	B7Z2V2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ACER3	ENST00000532485.6	TSL:1 MANE Select	c.45C>T	p.Thr15Thr	synonymous	Exon 1 of 11	ENSP00000434480.1	Q9NUN7-1
	ACER3	ENST00000278544.9	TSL:1	n.45C>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000278544.5	J3KN85
	ACER3	ENST00000525194.5	TSL:1	n.45C>T		non_coding_transcript_exon	Exon 1 of 11	ENSP00000432109.1	E9PKR3

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152160 Hom.: 2 Cov.: 31

Gnomad AFR AF: 0.00470

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

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: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000331 AC: 50 AN: 151162 AF XY: 0.000300

Gnomad AFR exome AF: 0.00509

Gnomad AMR exome AF: 0.000205

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000463

GnomAD4 exome AF: 0.000138 AC: 193 AN: 1395418 Hom.: 1 Cov.: 31 AF XY: 0.000118 AC XY: 81 AN XY: 688380

African (AFR) AF: 0.00503 AC: 158 AN: 31432

American (AMR) AF: 0.000365 AC: 13 AN: 35638

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25122

East Asian (EAS) AF: 0.00 AC: 0 AN: 35640

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79076

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48426

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4092

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078240

Other (OTH) AF: 0.000364 AC: 21 AN: 57752

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152278 Hom.: 2 Cov.: 31 AF XY: 0.00137 AC XY: 102 AN XY: 74472

African (AFR) AF: 0.00469 AC: 195 AN: 41578

American (AMR) AF: 0.000588 AC: 9 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67992

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000240 Hom.: 0

Bravo AF: 0.00156

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	ACER3-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.34
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		1.2
PromoterAI		-0.057	Neutral
Mutation Taster		=299/1	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: rs138662843; hg19: chr11-76572065;