8-18057200-C-T

Variant names:

• chr8-18057200-C-T
• rs115127411
• ENST00000314146.10:c.*334G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000314146.10(ASAH1):​c.*334G>A variant causes a splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0224 in 303,576 control chromosomes in the GnomAD database, including 108 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.025 (56 hom., cov: 32)
  • Exomes 𝑓: 0.020 (52 hom.)
• Consequence: ASAH1 ENST00000314146.10 splice_region
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.121
• Publications: 2 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=-0.87).
• BP6: Variant 8-18057200-C-T is Benign according to our data. Variant chr8-18057200-C-T is described in ClinVar as Benign. ClinVar VariationId is 362364.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0253 (3853/152266) while in subpopulation AFR AF = 0.047 (1953/41544). AF 95% confidence interval is 0.0453. There are 56 homozygotes in GnomAd4. There are 1927 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 56 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000314146.10. 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.*334G>A		3_prime_UTR	Exon 14 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.*334G>A		3_prime_UTR	Exon 14 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.*334G>A		3_prime_UTR	Exon 14 of 14	NP_001120977.1	Q13510-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000314146.10	TSL:1	c.*334G>A		splice_region	Exon 14 of 14	ENSP00000326970.10	Q13510-3
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.*334G>A		3_prime_UTR	Exon 14 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.*334G>A		3_prime_UTR	Exon 14 of 14	ENSP00000371152.4	Q13510-2

Frequencies

GnomAD3 genomes AF: 0.0253 AC: 3852 AN: 152148 Hom.: 56 Cov.: 32

Gnomad AFR AF: 0.0471

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0145

Gnomad ASJ AF: 0.0565

Gnomad EAS AF: 0.00250

Gnomad SAS AF: 0.0354

Gnomad FIN AF: 0.0325

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.0234

GnomAD4 exome AF: 0.0195 AC: 2958 AN: 151310 Hom.: 52 Cov.: 0 AF XY: 0.0208 AC XY: 1703 AN XY: 81916

African (AFR) AF: 0.0502 AC: 235 AN: 4678

American (AMR) AF: 0.0116 AC: 84 AN: 7230

Ashkenazi Jewish (ASJ) AF: 0.0570 AC: 205 AN: 3594

East Asian (EAS) AF: 0.00387 AC: 28 AN: 7226

South Asian (SAS) AF: 0.0344 AC: 986 AN: 28666

European-Finnish (FIN) AF: 0.0253 AC: 179 AN: 7072

Middle Eastern (MID) AF: 0.0308 AC: 17 AN: 552

European-Non Finnish (NFE) AF: 0.0127 AC: 1073 AN: 84652

Other (OTH) AF: 0.0198 AC: 151 AN: 7640

GnomAD4 genome AF: 0.0253 AC: 3853 AN: 152266 Hom.: 56 Cov.: 32 AF XY: 0.0259 AC XY: 1927 AN XY: 74464

African (AFR) AF: 0.0470 AC: 1953 AN: 41544

American (AMR) AF: 0.0144 AC: 221 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0565 AC: 196 AN: 3468

East Asian (EAS) AF: 0.00251 AC: 13 AN: 5180

South Asian (SAS) AF: 0.0354 AC: 171 AN: 4826

European-Finnish (FIN) AF: 0.0325 AC: 345 AN: 10602

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 899 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.00837 Hom.: 3

Bravo AF: 0.0243

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Farber lipogranulomatosis (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.9
DANN	Benign	0.62
PhyloP100		-0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism

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: rs115127411; hg19: chr8-17914709;