8-18061477-A-G

Variant names:

• chr8-18061477-A-G
• rs17515291
• NM_177924.5:c.704-19T>C

Variant summary

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

The NM_004315.6(ASAH1):​c.752-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.266 in 1,596,606 control chromosomes in the GnomAD database, including 59,237 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (4341 hom., cov: 32)
  • Exomes 𝑓: 0.27 (54896 hom.)
• Consequence: ASAH1 NM_004315.6 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.596
• Publications: 13 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

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

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 8-18061477-A-G is Benign according to our data. Variant chr8-18061477-A-G is described in ClinVar as Benign. ClinVar VariationId is 259282.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.353 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004315.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.704-19T>C		intron	N/A	NP_808592.2
	ASAH1	NM_004315.6		c.752-19T>C		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.686-19T>C		intron	N/A	NP_001120977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.704-19T>C		intron	N/A	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.752-19T>C		intron	N/A	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.686-19T>C		intron	N/A	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.227 AC: 34472 AN: 152042 Hom.: 4331 Cov.: 32

Gnomad AFR AF: 0.113

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.300

Gnomad ASJ AF: 0.321

Gnomad EAS AF: 0.315

Gnomad SAS AF: 0.367

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.247

Gnomad NFE AF: 0.260

Gnomad OTH AF: 0.245

GnomAD2 exomes AF: 0.281 AC: 70697 AN: 251196 AF XY: 0.283

Gnomad AFR exome AF: 0.109

Gnomad AMR exome AF: 0.429

Gnomad ASJ exome AF: 0.304

Gnomad EAS exome AF: 0.296

Gnomad FIN exome AF: 0.192

Gnomad NFE exome AF: 0.252

Gnomad OTH exome AF: 0.267

GnomAD4 exome AF: 0.270 AC: 389731 AN: 1444446 Hom.: 54896 Cov.: 30 AF XY: 0.273 AC XY: 196346 AN XY: 719954

African (AFR) AF: 0.104 AC: 3462 AN: 33236

American (AMR) AF: 0.413 AC: 18462 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.306 AC: 7960 AN: 26026

East Asian (EAS) AF: 0.343 AC: 13580 AN: 39614

South Asian (SAS) AF: 0.365 AC: 31334 AN: 85894

European-Finnish (FIN) AF: 0.196 AC: 10480 AN: 53398

Middle Eastern (MID) AF: 0.242 AC: 1390 AN: 5750

European-Non Finnish (NFE) AF: 0.262 AC: 286961 AN: 1095968

Other (OTH) AF: 0.269 AC: 16102 AN: 59862

GnomAD4 genome AF: 0.227 AC: 34503 AN: 152160 Hom.: 4341 Cov.: 32 AF XY: 0.230 AC XY: 17120 AN XY: 74396

African (AFR) AF: 0.113 AC: 4699 AN: 41534

American (AMR) AF: 0.301 AC: 4608 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.321 AC: 1115 AN: 3470

East Asian (EAS) AF: 0.315 AC: 1627 AN: 5162

South Asian (SAS) AF: 0.367 AC: 1771 AN: 4820

European-Finnish (FIN) AF: 0.204 AC: 2159 AN: 10594

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.260 AC: 17681 AN: 67968

Other (OTH) AF: 0.243 AC: 515 AN: 2116

Alfa AF: 0.253 Hom.: 22920

Bravo AF: 0.230

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	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	-0.89
CADD	Benign	5.6
DANN	Benign	0.45
PhyloP100		0.60
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs17515291; hg19: chr8-17918986;