rs200539084

Positions:

• chr19-18879354-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021267.5(CERS1):​c.787G>A​(p.Val263Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000842 in 1,590,956 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00062 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (1 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 7.40

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10771608).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CERS1	NM_021267.5	c.787G>A	p.Val263Ile	missense_variant	5/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-536G>A		5_prime_UTR_variant	5/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.787G>A	p.Val263Ile	missense_variant	5/8	1	NM_021267.5	ENSP00000485308.1
GDF1	ENST00000247005.8	c.-536G>A		5_prime_UTR_variant	5/8	1	NM_001492.6	ENSP00000247005.5

Frequencies

GnomAD3 genomes AF: 0.000625 AC: 95 AN: 152098 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000852

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00100

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000517 AC: 105 AN: 203122 Hom.: 0 AF XY: 0.000529 AC XY: 58 AN XY: 109736

Gnomad AFR exome AF: 0.000169

Gnomad AMR exome AF: 0.000593

Gnomad ASJ exome AF: 0.00162

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000111

Gnomad NFE exome AF: 0.000763

Gnomad OTH exome AF: 0.000190

GnomAD4 exome AF: 0.000865 AC: 1244 AN: 1438740 Hom.: 1 Cov.: 33 AF XY: 0.000830 AC XY: 592 AN XY: 713430

Gnomad4 AFR exome AF: 0.000272

Gnomad4 AMR exome AF: 0.000475

Gnomad4 ASJ exome AF: 0.00152

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000241

Gnomad4 FIN exome AF: 0.0000576

Gnomad4 NFE exome AF: 0.00102

Gnomad4 OTH exome AF: 0.000788

GnomAD4 genome AF: 0.000624 AC: 95 AN: 152216 Hom.: 0 Cov.: 32 AF XY: 0.000524 AC XY: 39 AN XY: 74422

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000851

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00100

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000737 Hom.: 0

Bravo AF: 0.000536

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000463 AC: 2

ESP6500EA AF: 0.000587 AC: 5

ExAC AF: 0.000390 AC: 47

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Progressive myoclonic epilepsy type 8 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jan 12, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 25, 2022	This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 263 of the CERS1 protein (p.Val263Ile). This variant is present in population databases (rs200539084, gnomAD 0.1%), 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: 475376). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt CERS1 protein function. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 27, 2021

The c.787G>A (p.V263I) alteration is located in exon 5 (coding exon 5) of the CERS1 gene. This alteration results from a G to A substitution at nucleotide position 787, causing the valine (V) at amino acid position 263 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

Jul 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.16
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.59	D;.;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.11	T;T;T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.83	.;N;N
REVEL	Uncertain	0.48
Sift	Benign	0.037	.;D;D
Sift4G	Benign	0.064	T;T;T
Polyphen		1.0	D;.;.
Vest4		0.43
MVP		0.65
ClinPred		0.075	T
GERP RS		3.7
Varity_R		0.17

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

Other links and lift over

dbSNP: rs200539084; hg19: chr19-18990163;