8-18056916-G-A

Variant names:

• chr8-18056916-G-A
• rs147840438
• NM_177924.5:c.*618C>T

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS1

The NM_177924.5(ASAH1):​c.*618C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 152,220 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASAH1 NM_177924.5 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.198

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]

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 8-18056916-G-A is Benign according to our data. Variant chr8-18056916-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2658455.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00294 (447/152220) while in subpopulation AFR AF = 0.0102 (425/41544). AF 95% confidence interval is 0.00943. There are 1 homozygotes in GnomAd4. There are 214 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_177924.5	c.*618C>T		3_prime_UTR_variant	Exon 14 of 14	ENST00000637790.2	NP_808592.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000637790.2	c.*618C>T		3_prime_UTR_variant	Exon 14 of 14	1	NM_177924.5	ENSP00000490272.1

Frequencies

GnomAD3 genomes AF: 0.00294 AC: 447 AN: 152102 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0103

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00239

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 464 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 258

African (AFR) AF: 0.00 AC: 0 AN: 2

American (AMR) AF: 0.00 AC: 0 AN: 60

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AF: 0.00 AC: 0 AN: 10

South Asian (SAS) AF: 0.00 AC: 0 AN: 30

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 346

Other (OTH) AF: 0.00 AC: 0 AN: 14

GnomAD4 genome AF: 0.00294 AC: 447 AN: 152220 Hom.: 1 Cov.: 32 AF XY: 0.00288 AC XY: 214 AN XY: 74416

African (AFR) AF: 0.0102 AC: 425 AN: 41544

American (AMR) AF: 0.000850 AC: 13 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10594

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68014

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00372

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ASAH1: BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	4.0
DANN	Benign	0.70
PhyloP100		0.20
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

Publications

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Other links and lift over

dbSNP: rs147840438; hg19: chr8-17914425;