rs2427746

Variant names:

• chr8-18069675-A-G
• rs2427746
• NM_177924.5:c.303+117T>C

Variant summary

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

The NM_177924.5(ASAH1):​c.303+117T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.387 in 705,090 control chromosomes in the GnomAD database, including 55,828 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11122 hom., cov: 32)
  • Exomes 𝑓: 0.39 (44706 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.340
• Publications: 6 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=-0.86).
• BP6: Variant 8-18069675-A-G is Benign according to our data. Variant chr8-18069675-A-G is described in ClinVar as Benign. ClinVar VariationId is 678030.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.442 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.303+117T>C		intron	N/A	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.351+117T>C		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.285+1625T>C		intron	N/A	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.303+117T>C		intron	N/A	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.351+117T>C		intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.285+1625T>C		intron	N/A	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.362 AC: 55057 AN: 151976 Hom.: 11104 Cov.: 32

Gnomad AFR AF: 0.175

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.427

Gnomad ASJ AF: 0.520

Gnomad EAS AF: 0.320

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.372

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.445

Gnomad OTH AF: 0.402

GnomAD4 exome AF: 0.394 AC: 217812 AN: 552998 Hom.: 44706 Cov.: 7 AF XY: 0.399 AC XY: 118201 AN XY: 296586

African (AFR) AF: 0.148 AC: 2390 AN: 16188

American (AMR) AF: 0.444 AC: 12497 AN: 28130

Ashkenazi Jewish (ASJ) AF: 0.473 AC: 7571 AN: 15992

East Asian (EAS) AF: 0.333 AC: 10593 AN: 31842

South Asian (SAS) AF: 0.436 AC: 24650 AN: 56594

European-Finnish (FIN) AF: 0.333 AC: 11462 AN: 34378

Middle Eastern (MID) AF: 0.379 AC: 1340 AN: 3540

European-Non Finnish (NFE) AF: 0.403 AC: 136063 AN: 337208

Other (OTH) AF: 0.386 AC: 11246 AN: 29126

GnomAD4 genome AF: 0.362 AC: 55097 AN: 152092 Hom.: 11122 Cov.: 32 AF XY: 0.363 AC XY: 26945 AN XY: 74330

African (AFR) AF: 0.175 AC: 7242 AN: 41500

American (AMR) AF: 0.427 AC: 6531 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.520 AC: 1801 AN: 3464

East Asian (EAS) AF: 0.320 AC: 1659 AN: 5180

South Asian (SAS) AF: 0.458 AC: 2209 AN: 4826

European-Finnish (FIN) AF: 0.372 AC: 3927 AN: 10546

Middle Eastern (MID) AF: 0.391 AC: 115 AN: 294

European-Non Finnish (NFE) AF: 0.445 AC: 30251 AN: 67976

Other (OTH) AF: 0.399 AC: 843 AN: 2112

Alfa AF: 0.414 Hom.: 7837

Bravo AF: 0.360

Asia WGS AF: 0.373 AC: 1298 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Farber lipogranulomatosis (1)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	5.4
DANN	Benign	0.58
PhyloP100		0.34
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: rs2427746; hg19: chr8-17927184;