8-18056822-ACTTC-A

Variant names:

• chr8-18056822-ACTTC-A
• rs35838806
• NM_177924.5:c.*708_*711delGAAG

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_177924.5(ASAH1):​c.*708_*711delGAAG variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.171 in 151,974 control chromosomes in the GnomAD database, including 3,492 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.17 (3492 hom., cov: 30)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: ASAH1 NM_177924.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.98
• 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 -10 ACMG points.

• BP6: Variant 8-18056822-ACTTC-A is Benign according to our data. Variant chr8-18056822-ACTTC-A is described in ClinVar as Benign. ClinVar VariationId is 362357.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.34 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.*708_*711delGAAG		3_prime_UTR	Exon 14 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.*708_*711delGAAG		3_prime_UTR	Exon 14 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.*708_*711delGAAG		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	ENST00000637790.2	TSL:1 MANE Select	c.*708_*711delGAAG		3_prime_UTR	Exon 14 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.*708_*711delGAAG		3_prime_UTR	Exon 14 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000637244.1	TSL:1	n.*2414_*2417delGAAG		non_coding_transcript_exon	Exon 14 of 14	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes AF: 0.171 AC: 25927 AN: 151856 Hom.: 3484 Cov.: 30

Gnomad AFR AF: 0.345

Gnomad AMI AF: 0.00769

Gnomad AMR AF: 0.235

Gnomad ASJ AF: 0.125

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.235

Gnomad FIN AF: 0.0800

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.0531

Gnomad OTH AF: 0.149

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 2 Hom.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

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

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.171 AC: 25968 AN: 151974 Hom.: 3492 Cov.: 30 AF XY: 0.177 AC XY: 13122 AN XY: 74300

African (AFR) AF: 0.345 AC: 14262 AN: 41352

American (AMR) AF: 0.235 AC: 3580 AN: 15232

Ashkenazi Jewish (ASJ) AF: 0.125 AC: 433 AN: 3468

East Asian (EAS) AF: 0.340 AC: 1756 AN: 5166

South Asian (SAS) AF: 0.236 AC: 1136 AN: 4822

European-Finnish (FIN) AF: 0.0800 AC: 848 AN: 10602

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0530 AC: 3608 AN: 68012

Other (OTH) AF: 0.147 AC: 311 AN: 2116

Alfa AF: 0.109 Hom.: 229

Bravo AF: 0.186

Asia WGS AF: 0.267 AC: 927 AN: 3472

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Farber lipogranulomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.0
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: rs35838806; hg19: chr8-17914331; COSMIC: COSV50502379; COSMIC: COSV50502379;