rs12675283

Variant names:

• chr8-18067340-C-T
• rs12675283
• NM_177924.5:c.304-42G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-18067340-C-T
• chr8-18067340-C-A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_177924.5(ASAH1):​c.304-42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.345 in 1,179,346 control chromosomes in the GnomAD database, including 73,235 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (9758 hom., cov: 31)
  • Exomes 𝑓: 0.34 (63477 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.54
• Publications: 4 publications found

Genes affected

ASAH1 (HGNC:735): (N-acylsphingosine amidohydrolase 1) This gene encodes a member of the acid ceramidase family of proteins. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed. Processing of this preproprotein generates alpha and beta subunits that heterodimerize to form the mature lysosomal enzyme, which catalyzes the degradation of ceramide into sphingosine and free fatty acid. This enzyme is overexpressed in multiple human cancers and may play a role in cancer progression. Mutations in this gene are associated with the lysosomal storage disorder, Farber lipogranulomatosis, and a neuromuscular disorder, spinal muscular atrophy with progressive myoclonic epilepsy. [provided by RefSeq, Oct 2015]

ASAH1 Gene-Disease associations (from GenCC):

• ASAH1-related sphingolipidosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• Farber lipogranulomatosis

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae), Orphanet
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Orphanet, G2P

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 8-18067340-C-T is Benign according to our data. Variant chr8-18067340-C-T is described in ClinVar as Benign. ClinVar VariationId is 259280.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.504 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_177924.5. 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
	ASAH1	NM_177924.5	MANE Select	c.304-42G>A		intron	N/A	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.352-42G>A		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.286-42G>A		intron	N/A	NP_001120977.1	Q13510-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.304-42G>A		intron	N/A	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.352-42G>A		intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.286-42G>A		intron	N/A	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.358 AC: 53156 AN: 148660 Hom.: 9759 Cov.: 31

Gnomad AFR AF: 0.291

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.444

Gnomad ASJ AF: 0.504

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.520

Gnomad FIN AF: 0.305

Gnomad MID AF: 0.336

Gnomad NFE AF: 0.364

Gnomad OTH AF: 0.360

GnomAD2 exomes AF: 0.345 AC: 37816 AN: 109580 AF XY: 0.357

Gnomad AFR exome AF: 0.201

Gnomad AMR exome AF: 0.448

Gnomad ASJ exome AF: 0.451

Gnomad EAS exome AF: 0.264

Gnomad FIN exome AF: 0.285

Gnomad NFE exome AF: 0.311

Gnomad OTH exome AF: 0.324

GnomAD4 exome AF: 0.343 AC: 353756 AN: 1030668 Hom.: 63477 Cov.: 14 AF XY: 0.347 AC XY: 178433 AN XY: 514074

African (AFR) AF: 0.250 AC: 5909 AN: 23626

American (AMR) AF: 0.470 AC: 9953 AN: 21190

Ashkenazi Jewish (ASJ) AF: 0.451 AC: 8541 AN: 18934

East Asian (EAS) AF: 0.370 AC: 11185 AN: 30194

South Asian (SAS) AF: 0.454 AC: 19486 AN: 42946

European-Finnish (FIN) AF: 0.266 AC: 10920 AN: 41032

Middle Eastern (MID) AF: 0.350 AC: 1336 AN: 3822

European-Non Finnish (NFE) AF: 0.337 AC: 271251 AN: 805760

Other (OTH) AF: 0.352 AC: 15175 AN: 43164

GnomAD4 genome AF: 0.358 AC: 53158 AN: 148678 Hom.: 9758 Cov.: 31 AF XY: 0.361 AC XY: 26178 AN XY: 72484

African (AFR) AF: 0.291 AC: 11905 AN: 40860

American (AMR) AF: 0.444 AC: 6608 AN: 14868

Ashkenazi Jewish (ASJ) AF: 0.504 AC: 1745 AN: 3464

East Asian (EAS) AF: 0.381 AC: 1956 AN: 5136

South Asian (SAS) AF: 0.521 AC: 2484 AN: 4770

European-Finnish (FIN) AF: 0.305 AC: 2753 AN: 9018

Middle Eastern (MID) AF: 0.324 AC: 90 AN: 278

European-Non Finnish (NFE) AF: 0.364 AC: 24512 AN: 67322

Other (OTH) AF: 0.358 AC: 735 AN: 2054

Alfa AF: 0.343 Hom.: 1880

Bravo AF: 0.365

Asia WGS AF: 0.397 AC: 1366 AN: 3438

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Farber lipogranulomatosis (1)
-	-	1	not specified (1)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.24
DANN	Benign	0.16
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12675283; hg19: chr8-17924849; COSMIC: COSV50502153; COSMIC: COSV50502153;