chr10-50245346-G-A

Position:

• chr10-50245346-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM1 PM2 BP4_Moderate

The NM_019893.4(ASAH2):​c.236C>T​(p.Ser79Phe) 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. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ASAH2 NM_019893.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.34

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM1: In a glycosylation_site O-linked (GalNAc...) serine (size 0) in uniprot entity ASAH2_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.12582046).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ASAH2	NM_019893.4	c.236C>T	p.Ser79Phe	missense_variant	3/21	ENST00000682911.1	NP_063946.2
ASAH2	NM_001143974.3	c.236C>T	p.Ser79Phe	missense_variant	3/20		NP_001137446.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ASAH2	ENST00000682911.1	c.236C>T	p.Ser79Phe	missense_variant	3/21		NM_019893.4	ENSP00000506746.1
ASAH2	ENST00000395526.9	c.236C>T	p.Ser79Phe	missense_variant	4/22	1		ENSP00000378897.3
ASAH2	ENST00000329428.10	c.179C>T	p.Ser60Phe	missense_variant	2/19	1		ENSP00000329886.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2021

The c.236C>T (p.S79F) alteration is located in exon 2 (coding exon 2) of the ASAH2 gene. This alteration results from a C to T substitution at nucleotide position 236, causing the serine (S) at amino acid position 79 to be replaced by a phenylalanine (F). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.61
CADD	Benign	17
DANN	Uncertain	0.99
DEOGEN2	Benign	0.26	T;.;.
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.73
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.52	T;T;T
M_CAP	Benign	0.0066	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.0	L;L;.
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-0.59	N;N;N
REVEL	Benign	0.081
Sift	Benign	0.044	D;D;D
Sift4G	Benign	0.088	T;T;T
Polyphen		0.64	P;P;.
Vest4		0.36
MutPred		0.22		Loss of glycosylation at S79 (P = 0.0028);Loss of glycosylation at S79 (P = 0.0028);.;
MVP		0.22
MPC		0.040
ClinPred		0.26	T
GERP RS		3.8
Varity_R		0.041
gMVP		0.42

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-52005106;