rs4921834

Variant names:

• chr8-18069785-C-T
• rs4921834
• NM_177924.5:c.303+7G>A

Your query was ambiguous. Multiple possible variants found:

• chr8-18069785-C-T
• chr8-18069785-C-G

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+7G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.466 in 1,510,636 control chromosomes in the GnomAD database, including 169,448 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14866 hom., cov: 32)
  • Exomes 𝑓: 0.47 (154582 hom.)
• Consequence: ASAH1 NM_177924.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002987
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.365
• 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: 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=-0.73).
• BP6: Variant 8-18069785-C-T is Benign according to our data. Variant chr8-18069785-C-T is described in ClinVar as Benign. ClinVar VariationId is 197388.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.518 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+7G>A		splice_region intron	N/A	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.351+7G>A		splice_region intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.285+1515G>A		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+7G>A		splice_region intron	N/A	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.351+7G>A		splice_region intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.285+1515G>A		intron	N/A	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65121 AN: 151788 Hom.: 14851 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.381

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.420

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.486

Gnomad OTH AF: 0.463

GnomAD2 exomes AF: 0.487 AC: 120346 AN: 247348 AF XY: 0.489

Gnomad AFR exome AF: 0.268

Gnomad AMR exome AF: 0.655

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.362

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.479

Gnomad OTH exome AF: 0.490

GnomAD4 exome AF: 0.471 AC: 639456 AN: 1358732 Hom.: 154582 Cov.: 25 AF XY: 0.475 AC XY: 323391 AN XY: 681082

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.256 AC: 8209 AN: 32092

American (AMR) AF: 0.639 AC: 28138 AN: 44044

Ashkenazi Jewish (ASJ) AF: 0.604 AC: 15181 AN: 25150

East Asian (EAS) AF: 0.400 AC: 15612 AN: 39042

South Asian (SAS) AF: 0.533 AC: 44532 AN: 83542

European-Finnish (FIN) AF: 0.406 AC: 20815 AN: 51216

Middle Eastern (MID) AF: 0.478 AC: 2643 AN: 5532

European-Non Finnish (NFE) AF: 0.468 AC: 477936 AN: 1021354

Other (OTH) AF: 0.465 AC: 26390 AN: 56760

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.429 AC: 65174 AN: 151904 Hom.: 14866 Cov.: 32 AF XY: 0.430 AC XY: 31904 AN XY: 74204

African (AFR) AF: 0.276 AC: 11440 AN: 41464

American (AMR) AF: 0.528 AC: 8052 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2147 AN: 3468

East Asian (EAS) AF: 0.382 AC: 1969 AN: 5160

South Asian (SAS) AF: 0.523 AC: 2521 AN: 4818

European-Finnish (FIN) AF: 0.420 AC: 4411 AN: 10506

Middle Eastern (MID) AF: 0.432 AC: 127 AN: 294

European-Non Finnish (NFE) AF: 0.486 AC: 33012 AN: 67914

Other (OTH) AF: 0.459 AC: 970 AN: 2112

Alfa AF: 0.467 Hom.: 11874

Bravo AF: 0.433

Asia WGS AF: 0.419 AC: 1455 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not provided (5)
-	-	5	not specified (5)
-	-	2	Farber lipogranulomatosis (2)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	7.0
DANN	Benign	0.75
PhyloP100		0.36
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000030
dbscSNV1_RF	Benign	0.0020
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: rs4921834; hg19: chr8-17927294; COSMIC: COSV50505501; COSMIC: COSV50505501;