8-18084755-C-T

Variant names:

• chr8-18084755-C-T
• rs200771465
• ENST00000381733.9:c.47G>A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_004315.6(ASAH1):​c.47G>A​(p.Arg16Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R16P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAH1 NM_004315.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.777

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

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.045558274).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ASAH1	NM_004315.6	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 14		NP_004306.3
ASAH1	NM_001127505.3	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 14		NP_001120977.1
ASAH1-AS1	NR_125429.1	n.-113C>T		upstream_gene_variant
ASAH1-AS1	NR_125430.1	n.-113C>T		upstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ASAH1	ENST00000381733.9	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 14	1		ENSP00000371152.4
ASAH1	ENST00000314146.10	c.47G>A	p.Arg16Gln	missense_variant	Exon 1 of 14	1		ENSP00000326970.10
ASAH1	ENST00000637244.1	n.47G>A		non_coding_transcript_exon_variant	Exon 1 of 14	1		ENSP00000490188.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	1.9
DANN	Benign	0.88
DEOGEN2	Benign	0.0065	.;T;.;.;.;T;T
Eigen	Benign	-1.9
Eigen_PC	Benign	-2.0
FATHMM_MKL	Benign	0.082	N
LIST_S2	Uncertain	0.86	D;D;D;D;D;D;T
M_CAP	Benign	0.023	T
MetaRNN	Benign	0.046	T;T;T;T;T;T;T
MetaSVM	Benign	-0.78	T
PrimateAI	Benign	0.19	T
PROVEAN	Benign	-0.080	N;.;.;N;.;.;.
REVEL	Benign	0.12
Sift	Benign	0.35	T;.;.;T;.;.;.
Sift4G	Benign	0.41	T;.;.;T;.;.;.
Polyphen		0.17	B;.;.;.;.;.;.
Vest4		0.12
MutPred		0.18		Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);Loss of phosphorylation at S18 (P = 0.0648);
MVP		0.25
MPC		0.0029
ClinPred		0.36	T
GERP RS		-6.5
gMVP		0.45

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs200771465; hg19: chr8-17942264;