rs113536478

Positions:

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_021267.5(CERS1):c.234T>C(p.Thr78=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.197 in 1,279,768 control chromosomes in the GnomAD database, including 27,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T78T) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.25 ( 5933 hom., cov: 31)

Exomes 𝑓: 0.19 ( 21713 hom. )

Consequence

CERS1
NM_021267.5 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.282

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 Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.79).

BP6

Variant 19-18895839-A-G is Benign according to our data. Variant chr19-18895839-A-G is described in ClinVar as [Benign]. Clinvar id is 137458.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.282 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.443 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CERS1	NM_021267.5 linkuse as main transcript	c.234T>C	p.Thr78=	synonymous_variant	1/8	ENST00000623882.4
GDF1	NM_001492.6 linkuse as main transcript	c.-1089T>C		5_prime_UTR_variant	1/8	ENST00000247005.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CERS1	ENST00000623882.4 linkuse as main transcript	c.234T>C	p.Thr78=	synonymous_variant	1/8	1	NM_021267.5	P2	P27544-1
CERS1	ENST00000429504.6 linkuse as main transcript	c.234T>C	p.Thr78=	synonymous_variant	1/6	1		A2	P27544-2
GDF1	ENST00000247005.8 linkuse as main transcript	c.-1089T>C		5_prime_UTR_variant	1/8	1	NM_001492.6	P1
CERS1	ENST00000542296.6 linkuse as main transcript	c.-46+722T>C		intron_variant		1

Frequencies

GnomAD3 genomes

AF:

0.249

AC:

37629

AN:

151126

Hom.:

5931

Cov.:

show subpopulations

Gnomad AFR

AF:

0.449

Gnomad AMI

AF:

0.0793

Gnomad AMR

AF:

0.183

Gnomad ASJ

AF:

0.196

Gnomad EAS

AF:

0.0724

Gnomad SAS

AF:

0.189

Gnomad FIN

AF:

0.101

Gnomad MID

AF:

0.156

Gnomad NFE

AF:

0.189

Gnomad OTH

AF:

0.219

GnomAD3 exomes

AF:

0.0966

AC:

1514

AN:

15678

Hom.:

AF XY:

0.103

AC XY:

1020

AN XY:

9940

show subpopulations

Gnomad AFR exome

AF:

0.281

Gnomad AMR exome

AF:

0.0522

Gnomad ASJ exome

AF:

0.105

Gnomad EAS exome

AF:

0.0248

Gnomad SAS exome

AF:

0.0955

Gnomad FIN exome

AF:

0.0626

Gnomad NFE exome

AF:

0.115

Gnomad OTH exome

AF:

0.0647

GnomAD4 exome

AF:

0.190

AC:

213914

AN:

1128532

Hom.:

21713

Cov.:

AF XY:

0.187

AC XY:

102406

AN XY:

547874

show subpopulations

Gnomad4 AFR exome

AF:

0.457

Gnomad4 AMR exome

AF:

0.138

Gnomad4 ASJ exome

AF:

0.171

Gnomad4 EAS exome

AF:

0.0752

Gnomad4 SAS exome

AF:

0.151

Gnomad4 FIN exome

AF:

0.104

Gnomad4 NFE exome

AF:

0.191

Gnomad4 OTH exome

AF:

0.190

GnomAD4 genome

AF:

0.249

AC:

37642

AN:

151236

Hom.:

5933

Cov.:

AF XY:

0.240

AC XY:

17709

AN XY:

73898

show subpopulations

Gnomad4 AFR

AF:

0.448

Gnomad4 AMR

AF:

0.183

Gnomad4 ASJ

AF:

0.196

Gnomad4 EAS

AF:

0.0724

Gnomad4 SAS

AF:

0.188

Gnomad4 FIN

AF:

0.101

Gnomad4 NFE

AF:

0.189

Gnomad4 OTH

AF:

0.216

Alfa

AF:

0.229

Hom.:

581

Bravo

AF:

0.262

Asia WGS

AF:

0.138

AC:

478

AN:

3458

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2016

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: MAF -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Progressive myoclonic epilepsy type 8

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.79

CADD

Benign

DANN

Benign

0.66

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

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