rs868136098

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The ENST00000623882.4(CERS1):c.37C>T(p.Pro13Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000213 in 989,926 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P13T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00085 ( 0 hom., cov: 30)

Exomes 𝑓: 0.00010 ( 0 hom. )

Consequence

CERS1
ENST00000623882.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3B:1

Conservation

PhyloP100: 0.981

Variant links:

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]

CERS1 links:

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]

GDF1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.07175419).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS1	NM_021267.5 linkuse as main transcript	c.37C>T	p.Pro13Ser	missense_variant	1/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6 linkuse as main transcript	c.-1286C>T		5_prime_UTR_variant	1/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4 linkuse as main transcript	c.37C>T	p.Pro13Ser	missense_variant	1/8	1	NM_021267.5	ENSP00000485308	P2	P27544-1
CERS1	ENST00000429504.6 linkuse as main transcript	c.37C>T	p.Pro13Ser	missense_variant	1/6	1		ENSP00000389044	A2	P27544-2
GDF1	ENST00000247005.8 linkuse as main transcript	c.-1286C>T		5_prime_UTR_variant	1/8	1	NM_001492.6	ENSP00000247005	P1
CERS1	ENST00000542296.6 linkuse as main transcript	c.-46+525C>T		intron_variant		1		ENSP00000437648

Frequencies

GnomAD3 genomes

AF:

0.000842

AC:

123

AN:

146108

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000272

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000456

Gnomad OTH

AF:

0.000992

GnomAD4 exome

AF:

0.000103

AC:

AN:

843714

Hom.:

Cov.:

AF XY:

0.0000921

AC XY:

AN XY:

391058

show subpopulations

Gnomad4 AFR exome

AF:

0.00339

Gnomad4 AMR exome

AF:

0.000724

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:

0.0000351

Gnomad4 OTH exome

AF:

0.000179

GnomAD4 genome

AF:

0.000848

AC:

124

AN:

146212

Hom.:

Cov.:

AF XY:

0.000787

AC XY:

AN XY:

71154

show subpopulations

Gnomad4 AFR

AF:

0.00281

Gnomad4 AMR

AF:

0.000271

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000456

Gnomad4 OTH

AF:

0.000981

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3Benign:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Progressive myoclonic epilepsy type 8

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 22, 2022	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 13 of the CERS1 protein (p.Pro13Ser). This variant is present in population databases (no rsID available, gnomAD 0.2%), and has an allele count higher than expected for a pathogenic variant. 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: 475369). 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: "Deleterious"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 26, 2024	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 12, 2023

The c.37C>T (p.P13S) alteration is located in exon 1 (coding exon 1) of the CERS1 gene. This alteration results from a C to T substitution at nucleotide position 37, causing the proline (P) at amino acid position 13 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

CERS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 28, 2023

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.50

BayesDel_noAF

Benign

-0.50

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.

Eigen

Benign

-0.45

Eigen_PC

Benign

-0.42

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.58

T;T

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.072

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

MutationTaster

Benign

1.0

D;N;N;D

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.68

.;N

REVEL

Benign

0.046

Sift

Benign

0.33

.;T

Sift4G

Benign

0.41

T;T

Polyphen

0.52

P;.

Vest4

0.23

MutPred

0.12

Gain of phosphorylation at P13 (P = 0.0267);Gain of phosphorylation at P13 (P = 0.0267);

MVP

0.13

ClinPred

0.13

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.066

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over