ENST00000381733.9:c.126+375A>C

Variant names:

• chr8-18084301-T-G
• rs114050279
• ENST00000381733.9:c.126+375A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The ENST00000381733.9(ASAH1):​c.126+375A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,429,818 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0080 (14 hom., cov: 33)
  • Exomes 𝑓: 0.00096 (5 hom.)
• Consequence: ASAH1 ENST00000381733.9 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.143
• Publications: 1 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-AS1 (HGNC:55603): (ASAH1 antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 8-18084301-T-G is Benign according to our data. Variant chr8-18084301-T-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1200164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00797 (1208/151606) while in subpopulation AFR AF = 0.0269 (1114/41338). AF 95% confidence interval is 0.0256. There are 14 homozygotes in GnomAd4. There are 571 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000381733.9. 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_004315.6		c.126+375A>C		intron	N/A	NP_004306.3
	ASAH1	NM_001127505.3		c.126+375A>C		intron	N/A	NP_001120977.1	Q13510-3
	ASAH1	NM_177924.5	MANE Select	c.-243A>C		upstream_gene	N/A	NP_808592.2	Q13510-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000381733.9	TSL:1	c.126+375A>C		intron	N/A	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.126+375A>C		intron	N/A	ENSP00000326970.10	Q13510-3
	ASAH1	ENST00000637244.1	TSL:1	n.*276A>C		non_coding_transcript_exon	Exon 1 of 14	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes AF: 0.00796 AC: 1206 AN: 151490 Hom.: 15 Cov.: 33

Gnomad AFR AF: 0.0270

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000354

Gnomad OTH AF: 0.00817

GnomAD4 exome AF: 0.000964 AC: 1232 AN: 1278212 Hom.: 5 Cov.: 31 AF XY: 0.000870 AC XY: 540 AN XY: 620356

African (AFR) AF: 0.0298 AC: 833 AN: 27990

American (AMR) AF: 0.00261 AC: 51 AN: 19516

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 18662

East Asian (EAS) AF: 0.0000291 AC: 1 AN: 34342

South Asian (SAS) AF: 0.0000481 AC: 3 AN: 62400

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29154

Middle Eastern (MID) AF: 0.00588 AC: 21 AN: 3572

European-Non Finnish (NFE) AF: 0.000193 AC: 199 AN: 1029556

Other (OTH) AF: 0.00234 AC: 124 AN: 53020

GnomAD4 genome AF: 0.00797 AC: 1208 AN: 151606 Hom.: 14 Cov.: 33 AF XY: 0.00771 AC XY: 571 AN XY: 74046

African (AFR) AF: 0.0269 AC: 1114 AN: 41338

American (AMR) AF: 0.00321 AC: 49 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5104

South Asian (SAS) AF: 0.00 AC: 0 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10510

Middle Eastern (MID) AF: 0.0137 AC: 4 AN: 292

European-Non Finnish (NFE) AF: 0.000354 AC: 24 AN: 67830

Other (OTH) AF: 0.00809 AC: 17 AN: 2102

Alfa AF: 0.0114 Hom.: 4

Bravo AF: 0.00962

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.3
DANN	Benign	0.54
PhyloP100		-0.14
PromoterAI		-0.057	Neutral
Mutation Taster		=300/0	polymorphism

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: rs114050279; hg19: chr8-17941810;