8-18061425-A-G

Variant names:

• chr8-18061425-A-G
• rs10103355
• NM_177924.5:c.737T>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.737T>C​(p.Val246Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.966 in 1,612,938 control chromosomes in the GnomAD database, including 758,609 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.88 (60692 hom., cov: 33)
  • Exomes 𝑓: 0.98 (697917 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 2.96
• Publications: 39 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=5.797227E-7).
• BP6: Variant 8-18061425-A-G is Benign according to our data. Variant chr8-18061425-A-G is described in ClinVar as Benign. ClinVar VariationId is 259283.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.985 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.737T>C	p.Val246Ala	missense	Exon 10 of 14	NP_808592.2
	ASAH1	NM_004315.6		c.785T>C	p.Val262Ala	missense	Exon 10 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.719T>C	p.Val240Ala	missense	Exon 10 of 14	NP_001120977.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.737T>C	p.Val246Ala	missense	Exon 10 of 14	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.785T>C	p.Val262Ala	missense	Exon 10 of 14	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.719T>C	p.Val240Ala	missense	Exon 10 of 14	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.878 AC: 133534 AN: 152090 Hom.: 60671 Cov.: 33

Gnomad AFR AF: 0.620

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.946

Gnomad ASJ AF: 0.996

Gnomad EAS AF: 0.876

Gnomad SAS AF: 0.963

Gnomad FIN AF: 0.964

Gnomad MID AF: 0.956

Gnomad NFE AF: 0.991

Gnomad OTH AF: 0.913

GnomAD2 exomes AF: 0.948 AC: 238477 AN: 251432 AF XY: 0.955

Gnomad AFR exome AF: 0.609

Gnomad AMR exome AF: 0.972

Gnomad ASJ exome AF: 0.994

Gnomad EAS exome AF: 0.869

Gnomad FIN exome AF: 0.967

Gnomad NFE exome AF: 0.991

Gnomad OTH exome AF: 0.963

GnomAD4 exome AF: 0.976 AC: 1425052 AN: 1460730 Hom.: 697917 Cov.: 46 AF XY: 0.976 AC XY: 709507 AN XY: 726806

African (AFR) AF: 0.609 AC: 20345 AN: 33434

American (AMR) AF: 0.969 AC: 43331 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.994 AC: 25972 AN: 26126

East Asian (EAS) AF: 0.898 AC: 35627 AN: 39686

South Asian (SAS) AF: 0.961 AC: 82901 AN: 86238

European-Finnish (FIN) AF: 0.968 AC: 51726 AN: 53418

Middle Eastern (MID) AF: 0.950 AC: 5482 AN: 5768

European-Non Finnish (NFE) AF: 0.992 AC: 1102174 AN: 1110988

Other (OTH) AF: 0.953 AC: 57494 AN: 60350

GnomAD4 genome AF: 0.878 AC: 133604 AN: 152208 Hom.: 60692 Cov.: 33 AF XY: 0.879 AC XY: 65396 AN XY: 74432

African (AFR) AF: 0.620 AC: 25697 AN: 41474

American (AMR) AF: 0.947 AC: 14480 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 3458 AN: 3472

East Asian (EAS) AF: 0.876 AC: 4539 AN: 5180

South Asian (SAS) AF: 0.963 AC: 4645 AN: 4822

European-Finnish (FIN) AF: 0.964 AC: 10237 AN: 10620

Middle Eastern (MID) AF: 0.956 AC: 281 AN: 294

European-Non Finnish (NFE) AF: 0.991 AC: 67431 AN: 68032

Other (OTH) AF: 0.914 AC: 1925 AN: 2106

Alfa AF: 0.959 Hom.: 213826

Bravo AF: 0.862

TwinsUK AF: 0.993 AC: 3683

ALSPAC AF: 0.992 AC: 3822

ESP6500AA AF: 0.624 AC: 2749

ESP6500EA AF: 0.991 AC: 8522

ExAC AF: 0.943 AC: 114493

Asia WGS AF: 0.902 AC: 3137 AN: 3478

EpiCase AF: 0.989

EpiControl AF: 0.990

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Farber lipogranulomatosis (2)
-	-	1	Farber lipogranulomatosis;C1834569:Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	20
DANN	Benign	0.84
DEOGEN2	Benign	0.39	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.54
FATHMM_MKL	Benign	0.37	N
LIST_S2	Benign	0.050	T
MetaRNN	Benign	5.8e-7	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	-2.4	N
PhyloP100		3.0
PrimateAI	Benign	0.38	T
PROVEAN	Benign	2.8	N
REVEL	Benign	0.26
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.042
MPC		0.0028
ClinPred		0.0082	T
GERP RS		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.035
gMVP		0.59
Mutation Taster		=97/3	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: rs10103355; hg19: chr8-17918934; COSMIC: COSV107253727; COSMIC: COSV107253727;