rs772627907

Positions:

• chr19-18884118-G-A
• chr19-18884118-G-C

Variant summary

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

The NM_021267.5(CERS1):​c.559C>T​(p.Leu187Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,356 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.04

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/exons	MANE	Protein	UniProt
CERS1	NM_021267.5	c.559C>T	p.Leu187Phe	missense_variant	3/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-764C>T		5_prime_UTR_variant	3/8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.559C>T	p.Leu187Phe	missense_variant	3/8	1	NM_021267.5	ENSP00000485308.1
GDF1	ENST00000247005.8	c.-764C>T		5_prime_UTR_variant	3/8	1	NM_001492.6	ENSP00000247005.5

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000407 AC: 1 AN: 245662 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 133620

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461356 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 726896

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	0.0078	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	16
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D;.;D
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.66	D;D;D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	.;N;D
REVEL	Uncertain	0.48
Sift	Benign	0.14	.;T;T
Sift4G	Benign	0.39	T;T;T
Polyphen		0.73	P;.;.
Vest4		0.55
MutPred		0.67		Loss of catalytic residue at T186 (P = 0.3817);Loss of catalytic residue at T186 (P = 0.3817);.;
MVP		0.56
ClinPred		0.48	T
GERP RS		-0.52
Varity_R		0.16

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: rs772627907; hg19: chr19-18994927;