NM_177924.5:c.277A>G

Variant names:

• chr8-18069818-T-C
• rs1049874
• NM_177924.5:c.277A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_177924.5(ASAH1):​c.277A>G​(p.Ile93Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.475 in 1,562,986 control chromosomes in the GnomAD database, including 181,906 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.43 (14946 hom., cov: 32)
  • Exomes 𝑓: 0.48 (166960 hom.)
• Consequence: ASAH1 NM_177924.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -1.77
• Publications: 49 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 -18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_177924.5
• BP4: Computational evidence support a benign effect (MetaRNN=3.8589424E-6).
• BP6: Variant 8-18069818-T-C is Benign according to our data. Variant chr8-18069818-T-C is described in ClinVar as Benign. ClinVar VariationId is 197389.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.277A>G	p.Ile93Val	missense	Exon 4 of 14	NP_808592.2
	ASAH1	NM_004315.6		c.325A>G	p.Ile109Val	missense	Exon 4 of 14	NP_004306.3
	ASAH1	NM_001363743.2		c.82A>G	p.Ile28Val	missense	Exon 4 of 14	NP_001350672.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH1	ENST00000637790.2	TSL:1 MANE Select	c.277A>G	p.Ile93Val	missense	Exon 4 of 14	ENSP00000490272.1
	ASAH1	ENST00000381733.9	TSL:1	c.325A>G	p.Ile109Val	missense	Exon 4 of 14	ENSP00000371152.4
	ASAH1	ENST00000314146.10	TSL:1	c.285+1482A>G		intron	N/A	ENSP00000326970.10

Frequencies

GnomAD3 genomes AF: 0.430 AC: 65269 AN: 151884 Hom.: 14930 Cov.: 32

Gnomad AFR AF: 0.276

Gnomad AMI AF: 0.577

Gnomad AMR AF: 0.528

Gnomad ASJ AF: 0.619

Gnomad EAS AF: 0.380

Gnomad SAS AF: 0.522

Gnomad FIN AF: 0.421

Gnomad MID AF: 0.434

Gnomad NFE AF: 0.487

Gnomad OTH AF: 0.464

GnomAD2 exomes AF: 0.489 AC: 121672 AN: 248828 AF XY: 0.492

Gnomad AFR exome AF: 0.270

Gnomad AMR exome AF: 0.656

Gnomad ASJ exome AF: 0.609

Gnomad EAS exome AF: 0.363

Gnomad FIN exome AF: 0.408

Gnomad NFE exome AF: 0.482

Gnomad OTH exome AF: 0.492

GnomAD4 exome AF: 0.480 AC: 676870 AN: 1410986 Hom.: 166960 Cov.: 30 AF XY: 0.483 AC XY: 339973 AN XY: 704054

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

African (AFR) AF: 0.261 AC: 8559 AN: 32776

American (AMR) AF: 0.640 AC: 28333 AN: 44280

Ashkenazi Jewish (ASJ) AF: 0.606 AC: 15523 AN: 25606

East Asian (EAS) AF: 0.401 AC: 15780 AN: 39304

South Asian (SAS) AF: 0.537 AC: 45573 AN: 84886

European-Finnish (FIN) AF: 0.410 AC: 21160 AN: 51664

Middle Eastern (MID) AF: 0.486 AC: 2746 AN: 5654

European-Non Finnish (NFE) AF: 0.479 AC: 511463 AN: 1068242

Other (OTH) AF: 0.473 AC: 27733 AN: 58574

⚠️ 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: 0.430 AC: 65324 AN: 152000 Hom.: 14946 Cov.: 32 AF XY: 0.430 AC XY: 31976 AN XY: 74278

African (AFR) AF: 0.276 AC: 11446 AN: 41446

American (AMR) AF: 0.528 AC: 8062 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.619 AC: 2145 AN: 3468

East Asian (EAS) AF: 0.380 AC: 1961 AN: 5156

South Asian (SAS) AF: 0.524 AC: 2529 AN: 4828

European-Finnish (FIN) AF: 0.421 AC: 4439 AN: 10550

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

European-Non Finnish (NFE) AF: 0.487 AC: 33117 AN: 67966

Other (OTH) AF: 0.461 AC: 972 AN: 2110

Alfa AF: 0.479 Hom.: 66948

Bravo AF: 0.434

TwinsUK AF: 0.482 AC: 1786

ALSPAC AF: 0.490 AC: 1887

ESP6500AA AF: 0.285 AC: 1253

ESP6500EA AF: 0.492 AC: 4229

ExAC AF: 0.479 AC: 58171

Asia WGS AF: 0.419 AC: 1458 AN: 3478

EpiCase AF: 0.501

EpiControl AF: 0.505

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Farber lipogranulomatosis (2)
-	-	1	Spinal muscular atrophy-progressive myoclonic epilepsy syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.82
CADD	Benign	0.0010
DANN	Benign	0.30
DEOGEN2	Benign	0.24	T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.013	N
LIST_S2	Benign	0.62	T
MetaRNN	Benign	0.0000039	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.015	N
PhyloP100		-1.8
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.23	N
REVEL	Benign	0.046
Sift	Benign	0.66	T
Sift4G	Benign	0.95	T
Polyphen		0.0	B
Vest4		0.015
MPC		0.0035
ClinPred		0.022	T
GERP RS		-11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.016
gMVP		0.72
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: rs1049874; hg19: chr8-17927327; COSMIC: COSV50501249; COSMIC: COSV50501249;