19-18879243-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_021267.5(CERS1):​c.898C>G​(p.Leu300Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000411 in 1,461,400 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Synonymous variant affecting the same amino acid position (i.e. L300L) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000041 ( 0 hom. )

Consequence

CERS1
NM_021267.5 missense, splice_region

Scores

8
11
Splicing: ADA: 0.008312
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 3.67
Variant links:
Genes affected
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]
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GDF1NM_001492.6 linkc.-425C>G splice_region_variant Exon 5 of 8 ENST00000247005.8 NP_001483.3 P27539A0A024R7N8
CERS1NM_021267.5 linkc.898C>G p.Leu300Val missense_variant, splice_region_variant Exon 5 of 8 ENST00000623882.4 NP_067090.1 P27544-1
GDF1NM_001492.6 linkc.-425C>G 5_prime_UTR_variant Exon 5 of 8 ENST00000247005.8 NP_001483.3 P27539A0A024R7N8

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GDF1ENST00000247005.8 linkc.-425C>G splice_region_variant Exon 5 of 8 1 NM_001492.6 ENSP00000247005.5 P27539
CERS1ENST00000623882.4 linkc.898C>G p.Leu300Val missense_variant, splice_region_variant Exon 5 of 8 1 NM_021267.5 ENSP00000485308.1 P27544-1
GDF1ENST00000247005.8 linkc.-425C>G 5_prime_UTR_variant Exon 5 of 8 1 NM_001492.6 ENSP00000247005.5 P27539

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000411
AC:
6
AN:
1461400
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726968
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000540
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Uncertain
0.030
T
BayesDel_noAF
Benign
-0.20
CADD
Uncertain
24
DANN
Benign
0.91
DEOGEN2
Uncertain
0.54
D;.;T
Eigen
Benign
-0.029
Eigen_PC
Benign
0.028
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Uncertain
0.87
D;D;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.51
D;D;D
MetaSVM
Benign
-0.56
T
MutationAssessor
Benign
0.65
N;N;.
PrimateAI
Uncertain
0.51
T
PROVEAN
Benign
-0.97
.;N;N
REVEL
Uncertain
0.36
Sift
Benign
0.58
.;T;T
Sift4G
Benign
0.34
T;T;T
Polyphen
0.72
P;.;.
Vest4
0.59
MutPred
0.63
Gain of catalytic residue at L300 (P = 0.1315);Gain of catalytic residue at L300 (P = 0.1315);.;
MVP
0.67
ClinPred
0.42
T
GERP RS
3.3
Varity_R
0.14

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.0083
dbscSNV1_RF
Benign
0.14
SpliceAI score (max)
0.18
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: chr19-18990052; API