rs6586684

Variant names:

• chr8-18067822-A-G
• rs6586684
• NM_177924.5:c.304-524T>C

Your query was ambiguous. Multiple possible variants found:

• chr8-18067822-A-G
• chr8-18067822-A-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177924.5(ASAH1):​c.304-524T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.347 in 152,168 control chromosomes in the GnomAD database, including 9,559 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.35 (9559 hom., cov: 32)
  • Exomes 𝑓: 0.14 (0 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.189
• Publications: 12 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 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.304-524T>C		intron	N/A	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.352-524T>C		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.286-524T>C		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.304-524T>C		intron	N/A	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.352-524T>C		intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.286-524T>C		intron	N/A	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.347 AC: 52818 AN: 152010 Hom.: 9550 Cov.: 32

Gnomad AFR AF: 0.262

Gnomad AMI AF: 0.407

Gnomad AMR AF: 0.443

Gnomad ASJ AF: 0.508

Gnomad EAS AF: 0.377

Gnomad SAS AF: 0.501

Gnomad FIN AF: 0.307

Gnomad MID AF: 0.326

Gnomad NFE AF: 0.363

Gnomad OTH AF: 0.354

GnomAD4 exome AF: 0.143 AC: 6 AN: 42 Hom.: 0 Cov.: 0 AF XY: 0.0938 AC XY: 3 AN XY: 32

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.500 AC: 1 AN: 2

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.139 AC: 5 AN: 36

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.348 AC: 52865 AN: 152126 Hom.: 9559 Cov.: 32 AF XY: 0.351 AC XY: 26071 AN XY: 74372

African (AFR) AF: 0.262 AC: 10864 AN: 41510

American (AMR) AF: 0.443 AC: 6772 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.508 AC: 1761 AN: 3468

East Asian (EAS) AF: 0.377 AC: 1946 AN: 5162

South Asian (SAS) AF: 0.502 AC: 2420 AN: 4824

European-Finnish (FIN) AF: 0.307 AC: 3246 AN: 10580

Middle Eastern (MID) AF: 0.320 AC: 94 AN: 294

European-Non Finnish (NFE) AF: 0.363 AC: 24649 AN: 67982

Other (OTH) AF: 0.351 AC: 742 AN: 2112

Alfa AF: 0.365 Hom.: 2381

Bravo AF: 0.356

Asia WGS AF: 0.398 AC: 1383 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.2
DANN	Benign	0.83
PhyloP100		0.19
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: rs6586684; hg19: chr8-17925331;