10-50214744-C-T

Variant names:

• chr10-50214744-C-T
• rs750753468
• NM_019893.4:c.1139G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_019893.4(ASAH2):​c.1139G>A​(p.Gly380Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000684 in 1,461,342 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. G380A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: ASAH2 NM_019893.4 missense, splice_region
• Scores: Splicing: ADA: 0.03980
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.20
• Publications: 0 publications found

Genes affected

ASAH2 (HGNC:18860): (N-acylsphingosine amidohydrolase 2) Ceramidases (EC 3.5.1.23), such as ASAH2, catalyze hydrolysis of the N-acyl linkage of ceramide, a second messenger in a variety of cellular events, to produce sphingosine. Sphingosine exerts both mitogenic and apoptosis-inducing activities, and its phosphorylated form functions as an intra- and intercellular second messenger (see MIM 603730) (Mitsutake et al., 2001 [PubMed 11328816]).[supplied by OMIM, Mar 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.787

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_019893.4. 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
	ASAH2	NM_019893.4	MANE Select	c.1139G>A	p.Gly380Glu	missense splice_region	Exon 9 of 21	NP_063946.2	Q9NR71-1
	ASAH2	NM_001143974.3		c.1139G>A	p.Gly380Glu	missense splice_region	Exon 9 of 20	NP_001137446.1	Q9NR71-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ASAH2	ENST00000682911.1	MANE Select	c.1139G>A	p.Gly380Glu	missense splice_region	Exon 9 of 21	ENSP00000506746.1	Q9NR71-1
	ASAH2	ENST00000395526.9	TSL:1	c.1139G>A	p.Gly380Glu	missense splice_region	Exon 10 of 22	ENSP00000378897.3	Q9NR71-1
	ASAH2	ENST00000329428.11	TSL:1	c.1139G>A	p.Gly380Glu	missense splice_region	Exon 8 of 19	ENSP00000329886.7

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461342 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726994

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

African (AFR) AF: 0.00 AC: 0 AN: 33450

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86246

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5760

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111618

Other (OTH) AF: 0.00 AC: 0 AN: 60346

⚠️ 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 Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.059	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Benign	-0.85	T
PhyloP100		7.2
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.29
Sift	Benign	0.18	T
Sift4G	Benign	0.26	T
Polyphen		1.0	D
Vest4		0.73
MutPred		0.64		Loss of sheet (P = 0.0817)
MVP		0.46
MPC		3.8
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.55
gMVP		0.78
Mutation Taster		=36/64	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.040
dbscSNV1_RF	Benign	0.43
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: rs750753468; hg19: chr10-51974504;