rs902153714
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3
The NM_021267.5(CERS1):c.708T>A(p.His236Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,553,170 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).
Frequency
Genomes: 𝑓 0.000072 ( 0 hom., cov: 31)
Exomes 𝑓: 0.000011 ( 0 hom. )
Consequence
CERS1
NM_021267.5 missense
NM_021267.5 missense
Scores
1
5
10
Clinical Significance
Conservation
PhyloP100: 0.120
Genes affected
CERS1 (HGNC:14253): (ceramide synthase 1) This gene encodes a ceramide synthase enzyme, which catalyzes the synthesis of ceramide, the hydrophobic moiety of sphingolipids. The encoded enzyme synthesizes 18-carbon (C18) ceramide in brain neurons. Elevated expression of this gene may be associated with increased longevity, while decreased expression of this gene may be associated with myoclonus epilepsy with dementia in human patients. This protein is transcribed from a monocistronic mRNA as well as a bicistronic mRNA, which also encodes growth differentiation factor 1. [provided by RefSeq, Jul 2016]
GDF1 (HGNC:4214): (growth differentiation factor 1) This gene encodes a secreted ligand of the TGF-beta (transforming growth factor-beta) superfamily of proteins. Ligands of this family bind various TGF-beta receptors leading to recruitment and activation of SMAD family transcription factors that regulate gene expression. The encoded preproprotein is proteolytically processed to generate each subunit of the disulfide-linked homodimer. Studies in rodents suggest that this protein is involved in the establishment of left-right asymmetry in early embryogenesis and in neural development in later embryogenesis. The encoded protein is translated from a bicistronic mRNA that also encodes ceramide synthase 1. Mutations in this gene are associated with several congenital cardiovascular malformations. [provided by RefSeq, Jul 2016]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 3 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.769
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
CERS1 | NM_021267.5 | c.708T>A | p.His236Gln | missense_variant | 4/8 | ENST00000623882.4 | |
GDF1 | NM_001492.6 | c.-615T>A | 5_prime_UTR_variant | 4/8 | ENST00000247005.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
CERS1 | ENST00000623882.4 | c.708T>A | p.His236Gln | missense_variant | 4/8 | 1 | NM_021267.5 | P2 | |
GDF1 | ENST00000247005.8 | c.-615T>A | 5_prime_UTR_variant | 4/8 | 1 | NM_001492.6 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000657 AC: 10AN: 152188Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.0000129 AC: 2AN: 155440Hom.: 0 AF XY: 0.0000121 AC XY: 1AN XY: 82714
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GnomAD4 exome AF: 0.0000114 AC: 16AN: 1400864Hom.: 0 Cov.: 31 AF XY: 0.00000579 AC XY: 4AN XY: 691218
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GnomAD4 genome ? AF: 0.0000722 AC: 11AN: 152306Hom.: 0 Cov.: 31 AF XY: 0.000107 AC XY: 8AN XY: 74476
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2023 | The c.708T>A (p.H236Q) alteration is located in exon 4 (coding exon 4) of the CERS1 gene. This alteration results from a T to A substitution at nucleotide position 708, causing the histidine (H) at amino acid position 236 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Progressive myoclonic epilepsy type 8 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Dec 02, 2021 | This sequence change replaces histidine, which is basic and polar, with glutamine, which is neutral and polar, at codon 236 of the CERS1 protein (p.His236Gln). This variant is present in population databases (no rsID available, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with CERS1-related conditions. ClinVar contains an entry for this variant (Variation ID: 542126). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
DEOGEN2
Uncertain
D;.;D
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Benign
T;T;T
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D;D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;M;.
MutationTaster
Benign
N;N;N;D
PrimateAI
Uncertain
T
Sift4G
Benign
T;T;T
Polyphen
P;.;.
Vest4
MutPred
Loss of methylation at R234 (P = 0.0554);Loss of methylation at R234 (P = 0.0554);.;
MVP
ClinPred
T
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at