rs2472205

Variant names:

• chr8-18067230-A-T
• rs2472205
• NM_177924.5:c.372T>A

Your query was ambiguous. Multiple possible variants found:

• chr8-18067230-A-T
• chr8-18067230-A-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.372T>A​(p.Asp124Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0407 in 1,605,582 control chromosomes in the GnomAD database, including 1,602 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D124A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.034 (118 hom., cov: 31)
  • Exomes 𝑓: 0.041 (1484 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -1.24
• Publications: 12 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 (MetaRNN=0.0013536811).
• BP6: Variant 8-18067230-A-T is Benign according to our data. Variant chr8-18067230-A-T is described in ClinVar as Benign. ClinVar VariationId is 362381.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0513 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.372T>A	p.Asp124Glu	missense	Exon 5 of 14	NP_808592.2	Q13510-1
	ASAH1	NM_004315.6		c.420T>A	p.Asp140Glu	missense	Exon 5 of 14	NP_004306.3
	ASAH1	NM_001127505.3		c.354T>A	p.Asp118Glu	missense	Exon 5 of 14	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.372T>A	p.Asp124Glu	missense	Exon 5 of 14	ENSP00000490272.1	Q13510-1
	ASAH1	ENST00000381733.9	TSL:1	c.420T>A	p.Asp140Glu	missense	Exon 5 of 14	ENSP00000371152.4	Q13510-2
	ASAH1	ENST00000314146.10	TSL:1	c.354T>A	p.Asp118Glu	missense	Exon 5 of 14	ENSP00000326970.10	Q13510-3

Frequencies

GnomAD3 genomes AF: 0.0337 AC: 5016 AN: 148786 Hom.: 118 Cov.: 31

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0250

Gnomad ASJ AF: 0.0705

Gnomad EAS AF: 0.000777

Gnomad SAS AF: 0.0572

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0452

Gnomad OTH AF: 0.0320

GnomAD2 exomes AF: 0.0388 AC: 9709 AN: 249922 AF XY: 0.0421

Gnomad AFR exome AF: 0.0108

Gnomad AMR exome AF: 0.0162

Gnomad ASJ exome AF: 0.0683

Gnomad EAS exome AF: 0.000708

Gnomad FIN exome AF: 0.0472

Gnomad NFE exome AF: 0.0442

Gnomad OTH exome AF: 0.0448

GnomAD4 exome AF: 0.0414 AC: 60273 AN: 1456692 Hom.: 1484 Cov.: 32 AF XY: 0.0424 AC XY: 30728 AN XY: 724554

African (AFR) AF: 0.0106 AC: 354 AN: 33442

American (AMR) AF: 0.0185 AC: 827 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0671 AC: 1740 AN: 25922

East Asian (EAS) AF: 0.000303 AC: 12 AN: 39648

South Asian (SAS) AF: 0.0646 AC: 5516 AN: 85346

European-Finnish (FIN) AF: 0.0468 AC: 2483 AN: 53018

Middle Eastern (MID) AF: 0.0473 AC: 272 AN: 5748

European-Non Finnish (NFE) AF: 0.0421 AC: 46631 AN: 1108864

Other (OTH) AF: 0.0406 AC: 2438 AN: 60102

GnomAD4 genome AF: 0.0337 AC: 5015 AN: 148890 Hom.: 118 Cov.: 31 AF XY: 0.0343 AC XY: 2489 AN XY: 72652

African (AFR) AF: 0.0109 AC: 449 AN: 41008

American (AMR) AF: 0.0249 AC: 373 AN: 14966

Ashkenazi Jewish (ASJ) AF: 0.0705 AC: 242 AN: 3432

East Asian (EAS) AF: 0.000779 AC: 4 AN: 5132

South Asian (SAS) AF: 0.0569 AC: 268 AN: 4714

European-Finnish (FIN) AF: 0.0500 AC: 494 AN: 9876

Middle Eastern (MID) AF: 0.0171 AC: 5 AN: 292

European-Non Finnish (NFE) AF: 0.0452 AC: 3009 AN: 66522

Other (OTH) AF: 0.0322 AC: 66 AN: 2050

Alfa AF: 0.0410 Hom.: 93

Bravo AF: 0.0297

TwinsUK AF: 0.0410 AC: 152

ALSPAC AF: 0.0413 AC: 159

ESP6500AA AF: 0.0136 AC: 60

ESP6500EA AF: 0.0450 AC: 387

ExAC AF: 0.0414 AC: 5022

Asia WGS AF: 0.0250 AC: 90 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	3	not specified (3)
-	-	1	Farber lipogranulomatosis (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.67	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.7
DANN	Benign	0.97
DEOGEN2	Benign	0.31	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.039	N
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0014	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.29	N
PhyloP100		-1.2
PrimateAI	Benign	0.23	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.064
Sift	Benign	0.12	T
Sift4G	Benign	0.095	T
Polyphen		0.0	B
Vest4		0.069
MutPred		0.15		Gain of solvent accessibility (P = 0.2601)
MPC		0.0033
ClinPred		0.0035	T
GERP RS		-2.9
Varity_R		0.12
gMVP		0.77
Mutation Taster		=99/1	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: rs2472205; hg19: chr8-17924739; COSMIC: COSV107253771;