8-18084687-CAGCAAAG-C

Variant names:

• chr8-18084687-CAGCAAAG-C
• rs548868946
• ENST00000381733.9:c.108_114delCTTTGCT

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 10P and 5B. PVS1 PM2 BP6 BS1

The NM_004315.6(ASAH1):​c.108_114delCTTTGCT​(p.Ser36ArgfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00027 in 1,613,676 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: ASAH1 NM_004315.6 frameshift
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 0.545

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-AS1 (HGNC:55603): (ASAH1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 5 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• BP6: Variant 8-18084687-CAGCAAAG-C is Benign according to our data. Variant chr8-18084687-CAGCAAAG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1695223.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=1}.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00141 (215/152332) while in subpopulation AFR AF= 0.00491 (204/41580). AF 95% confidence interval is 0.00435. There are 1 homozygotes in gnomad4. There are 108 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.108_114delCTTTGCT	p.Ser36ArgfsTer2	frameshift_variant	Exon 1 of 14		NP_004306.3
ASAH1	NM_001127505.3	c.108_114delCTTTGCT	p.Ser36ArgfsTer2	frameshift_variant	Exon 1 of 14		NP_001120977.1
ASAH1-AS1	NR_125429.1	n.-180_-174delAGCAAAG		upstream_gene_variant
ASAH1-AS1	NR_125430.1	n.-180_-174delAGCAAAG		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.108_114delCTTTGCT	p.Ser36ArgfsTer2	frameshift_variant	Exon 1 of 14	1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.108_114delCTTTGCT	p.Ser36ArgfsTer2	frameshift_variant	Exon 1 of 14	1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.108_114delCTTTGCT		non_coding_transcript_exon_variant	Exon 1 of 14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes AF: 0.00141 AC: 214 AN: 152214 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00490

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000341 AC: 85 AN: 249026 Hom.: 0 AF XY: 0.000297 AC XY: 40 AN XY: 134704

Gnomad AFR exome AF: 0.00428

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000447

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000151 AC: 220 AN: 1461344 Hom.: 0 AF XY: 0.000127 AC XY: 92 AN XY: 726888

Gnomad4 AFR exome AF: 0.00487

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000162

Gnomad4 OTH exome AF: 0.000315

GnomAD4 genome AF: 0.00141 AC: 215 AN: 152332 Hom.: 1 Cov.: 33 AF XY: 0.00145 AC XY: 108 AN XY: 74482

Gnomad4 AFR AF: 0.00491

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000738 Hom.: 0

Bravo AF: 0.00165

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1

May 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 24, 2024

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs548868946; hg19: chr8-17942196;