8-18084695-C-T

Variant names:

• chr8-18084695-C-T
• rs13263632
• ENST00000381733.9:c.107G>A

Variant summary

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

The NM_004315.6(ASAH1):​c.107G>A​(p.Ser36Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0526 in 1,613,174 control chromosomes in the GnomAD database, including 2,862 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.075 (600 hom., cov: 33)
  • Exomes 𝑓: 0.050 (2262 hom.)
• Consequence: ASAH1 NM_004315.6 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.139
• Publications: 16 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 (MetaRNN=0.0017465055).
• BP6: Variant 8-18084695-C-T is Benign according to our data. Variant chr8-18084695-C-T is described in ClinVar as Benign. ClinVar VariationId is 558960.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.145 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004315.6. 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.107G>A	p.Ser36Asn	missense	Exon 1 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.107G>A	p.Ser36Asn	missense	Exon 1 of 14	NP_001120977.1	Q13510-3
	ASAH1-AS1	NR_125429.1		n.-173C>T		upstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000381733.9	TSL:1	c.107G>A	p.Ser36Asn	missense	Exon 1 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.107G>A	p.Ser36Asn	missense	Exon 1 of 14	ENSP00000326970.10	Q13510-3
	ASAH1	ENST00000637244.1	TSL:1	n.107G>A		non_coding_transcript_exon	Exon 1 of 14	ENSP00000490188.1	A0A1B0GUP1

Frequencies

GnomAD3 genomes AF: 0.0743 AC: 11282 AN: 151790 Hom.: 592 Cov.: 33

Gnomad AFR AF: 0.147

Gnomad AMI AF: 0.170

Gnomad AMR AF: 0.0378

Gnomad ASJ AF: 0.0248

Gnomad EAS AF: 0.0529

Gnomad SAS AF: 0.0616

Gnomad FIN AF: 0.0343

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0492

Gnomad OTH AF: 0.0583

GnomAD2 exomes AF: 0.0493 AC: 12266 AN: 248932 AF XY: 0.0481

Gnomad AFR exome AF: 0.144

Gnomad AMR exome AF: 0.0193

Gnomad ASJ exome AF: 0.0236

Gnomad EAS exome AF: 0.0508

Gnomad FIN exome AF: 0.0323

Gnomad NFE exome AF: 0.0481

Gnomad OTH exome AF: 0.0394

GnomAD4 exome AF: 0.0504 AC: 73600 AN: 1461268 Hom.: 2262 Cov.: 31 AF XY: 0.0505 AC XY: 36716 AN XY: 726822

African (AFR) AF: 0.151 AC: 5070 AN: 33470

American (AMR) AF: 0.0211 AC: 942 AN: 44662

Ashkenazi Jewish (ASJ) AF: 0.0240 AC: 627 AN: 26118

East Asian (EAS) AF: 0.0747 AC: 2966 AN: 39696

South Asian (SAS) AF: 0.0594 AC: 5114 AN: 86054

European-Finnish (FIN) AF: 0.0343 AC: 1829 AN: 53378

Middle Eastern (MID) AF: 0.0310 AC: 179 AN: 5766

European-Non Finnish (NFE) AF: 0.0484 AC: 53802 AN: 1111742

Other (OTH) AF: 0.0509 AC: 3071 AN: 60382

GnomAD4 genome AF: 0.0745 AC: 11322 AN: 151906 Hom.: 600 Cov.: 33 AF XY: 0.0729 AC XY: 5413 AN XY: 74272

African (AFR) AF: 0.148 AC: 6098 AN: 41194

American (AMR) AF: 0.0377 AC: 577 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.0248 AC: 86 AN: 3472

East Asian (EAS) AF: 0.0526 AC: 273 AN: 5186

South Asian (SAS) AF: 0.0617 AC: 297 AN: 4816

European-Finnish (FIN) AF: 0.0343 AC: 364 AN: 10614

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0492 AC: 3347 AN: 68012

Other (OTH) AF: 0.0572 AC: 121 AN: 2114

Alfa AF: 0.0561 Hom.: 1140

Bravo AF: 0.0770

TwinsUK AF: 0.0415 AC: 154

ALSPAC AF: 0.0446 AC: 172

ESP6500AA AF: 0.145 AC: 640

ESP6500EA AF: 0.0484 AC: 416

ExAC AF: 0.0538 AC: 6535

Asia WGS AF: 0.0550 AC: 192 AN: 3478

EpiCase AF: 0.0430

EpiControl AF: 0.0415

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	6.1
DANN	Benign	0.87
DEOGEN2	Benign	0.018	T
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.74	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.1	T
PhyloP100		-0.14
PrimateAI	Benign	0.34	T
PROVEAN	Benign	-0.97	N
REVEL	Benign	0.099
Sift	Benign	0.45	T
Sift4G	Benign	0.46	T
Polyphen		0.0070	B
Vest4		0.040
MPC		0.0033
ClinPred		0.0055	T
GERP RS		0.22
PromoterAI		-0.0096	Neutral
gMVP		0.30
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs13263632; hg19: chr8-17942204;