12-50134672-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_147190.5(CERS5):​c.903G>C​(p.Trp301Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Consequence

CERS5
NM_147190.5 missense

Scores

9
7
3

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.79
Variant links:
Genes affected
CERS5 (HGNC:23749): (ceramide synthase 5) This gene encodes a protein that belongs to the TLC (TRAM, LAG1 and CLN8 homology domains) family of proteins. The encoded protein functions in the synthesis of ceramide, a lipid molecule that is involved in a several cellular signaling pathways. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.871

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CERS5NM_147190.5 linkc.903G>C p.Trp301Cys missense_variant Exon 9 of 10 ENST00000317551.12 NP_671723.1 Q8N5B7-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CERS5ENST00000317551.12 linkc.903G>C p.Trp301Cys missense_variant Exon 9 of 10 2 NM_147190.5 ENSP00000325485.6 Q8N5B7-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
May 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.903G>C (p.W301C) alteration is located in exon 9 (coding exon 9) of the CERS5 gene. This alteration results from a G to C substitution at nucleotide position 903, causing the tryptophan (W) at amino acid position 301 to be replaced by a cysteine (C). 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
Pathogenic
0.85
BayesDel_addAF
Pathogenic
0.43
D
BayesDel_noAF
Pathogenic
0.38
CADD
Pathogenic
28
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.65
.;D
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.97
D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Pathogenic
0.87
D;D
MetaSVM
Uncertain
0.61
D
MutationAssessor
Pathogenic
3.5
.;M
PrimateAI
Uncertain
0.75
T
PROVEAN
Pathogenic
-6.5
D;D
REVEL
Pathogenic
0.85
Sift
Benign
0.18
T;D
Sift4G
Benign
0.17
T;T
Polyphen
0.98
.;D
Vest4
0.84
MutPred
0.59
.;Gain of catalytic residue at I304 (P = 0.0028);
MVP
0.94
MPC
1.4
ClinPred
0.99
D
GERP RS
5.0
Varity_R
0.80
gMVP
0.89

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: chr12-50528455; API