rs373056917

Variant names:

• chr19-18880341-C-T
• rs373056917
• NM_021267.5:c.685G>A

Variant summary

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

The NM_021267.5(CERS1):​c.685G>A​(p.Gly229Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000187 in 1,557,914 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00021 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 7.25

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]

ACMG classification

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
CERS1	NM_021267.5	c.685G>A	p.Gly229Ser	missense_variant	Exon 4 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-638G>A		5_prime_UTR_variant	Exon 4 of 8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.685G>A	p.Gly229Ser	missense_variant	Exon 4 of 8	1	NM_021267.5	ENSP00000485308.1
GDF1	ENST00000247005.8	c.-638G>A		5_prime_UTR_variant	Exon 4 of 8	1	NM_001492.6	ENSP00000247005.5

Frequencies

GnomAD3 genomes AF: 0.000210 AC: 32 AN: 152192 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000179 AC: 29 AN: 162400 Hom.: 0 AF XY: 0.000162 AC XY: 14 AN XY: 86638

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000431

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000373

Gnomad OTH exome AF: 0.000877

GnomAD4 exome AF: 0.000185 AC: 260 AN: 1405722 Hom.: 0 Cov.: 31 AF XY: 0.000200 AC XY: 139 AN XY: 694050

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000552

Gnomad4 ASJ exome AF: 0.0000396

Gnomad4 EAS exome AF: 0.0000275

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000201

Gnomad4 NFE exome AF: 0.000219

Gnomad4 OTH exome AF: 0.000189

GnomAD4 genome AF: 0.000210 AC: 32 AN: 152192 Hom.: 0 Cov.: 31 AF XY: 0.000188 AC XY: 14 AN XY: 74356

Gnomad4 AFR AF: 0.0000483

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000192

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000353

Gnomad4 OTH AF: 0.000956

Alfa AF: 0.000245 Hom.: 0

Bravo AF: 0.000215

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000120 AC: 1

ExAC AF: 0.000102 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Apr 25, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.685G>A (p.G229S) alteration is located in exon 4 (coding exon 4) of the CERS1 gene. This alteration results from a G to A substitution at nucleotide position 685, causing the glycine (G) at amino acid position 229 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Progressive myoclonic epilepsy type 8 Uncertain:1

Oct 05, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glycine, which is neutral and non-polar, with serine, which is neutral and polar, at codon 229 of the CERS1 protein (p.Gly229Ser). This variant is present in population databases (rs373056917, 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: 571809). 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: "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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.86	D;.;D
Eigen	Uncertain	0.28
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Uncertain	0.55	D;D;D
MetaSVM	Benign	-0.65	T
MutationAssessor	Pathogenic	3.0	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.8	.;D;D
REVEL	Benign	0.28
Sift	Benign	0.035	.;D;D
Sift4G	Uncertain	0.033	D;D;T
Polyphen		0.96	D;.;.
Vest4		0.65
MVP		0.48
ClinPred		0.36	T
GERP RS		3.9
Varity_R		0.18

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs373056917; hg19: chr19-18991150;