8-18064905-A-G

Variant names:

• chr8-18064905-A-G
• rs7830490
• NM_177924.5:c.383-374T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_177924.5(ASAH1):​c.383-374T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.628 in 176,556 control chromosomes in the GnomAD database, including 35,268 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.63 (30634 hom., cov: 33)
  • Exomes 𝑓: 0.61 (4634 hom.)
• Consequence: ASAH1 NM_177924.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• Publications: 9 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: G2P, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• spinal muscular atrophy-progressive myoclonic epilepsy syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Genomics England PanelApp, G2P

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.674 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	NM_177924.5	MANE Select	c.383-374T>C		intron	N/A	NP_808592.2
	ASAH1	NM_004315.6		c.431-374T>C		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.365-374T>C		intron	N/A	NP_001120977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.383-374T>C		intron	N/A	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.431-374T>C		intron	N/A	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.365-374T>C		intron	N/A	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.632 AC: 95969 AN: 151908 Hom.: 30616 Cov.: 33

Gnomad AFR AF: 0.681

Gnomad AMI AF: 0.595

Gnomad AMR AF: 0.550

Gnomad ASJ AF: 0.501

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.470

Gnomad FIN AF: 0.663

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.644

Gnomad OTH AF: 0.633

GnomAD4 exome AF: 0.605 AC: 14841 AN: 24530 Hom.: 4634 Cov.: 0 AF XY: 0.597 AC XY: 7578 AN XY: 12698

African (AFR) AF: 0.690 AC: 505 AN: 732

American (AMR) AF: 0.456 AC: 932 AN: 2044

Ashkenazi Jewish (ASJ) AF: 0.528 AC: 399 AN: 756

East Asian (EAS) AF: 0.500 AC: 667 AN: 1334

South Asian (SAS) AF: 0.449 AC: 911 AN: 2030

European-Finnish (FIN) AF: 0.683 AC: 470 AN: 688

Middle Eastern (MID) AF: 0.679 AC: 76 AN: 112

European-Non Finnish (NFE) AF: 0.650 AC: 10063 AN: 15486

Other (OTH) AF: 0.607 AC: 818 AN: 1348

GnomAD4 genome AF: 0.632 AC: 96037 AN: 152026 Hom.: 30634 Cov.: 33 AF XY: 0.626 AC XY: 46521 AN XY: 74330

African (AFR) AF: 0.681 AC: 28198 AN: 41428

American (AMR) AF: 0.550 AC: 8397 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.501 AC: 1739 AN: 3470

East Asian (EAS) AF: 0.503 AC: 2608 AN: 5180

South Asian (SAS) AF: 0.470 AC: 2263 AN: 4820

European-Finnish (FIN) AF: 0.663 AC: 6994 AN: 10552

Middle Eastern (MID) AF: 0.663 AC: 195 AN: 294

European-Non Finnish (NFE) AF: 0.644 AC: 43759 AN: 67984

Other (OTH) AF: 0.635 AC: 1341 AN: 2112

Alfa AF: 0.629 Hom.: 15498

Bravo AF: 0.622

Asia WGS AF: 0.533 AC: 1855 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	9.5
DANN	Benign	0.53
PhyloP100		0.34
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs7830490; hg19: chr8-17922414;