19-18880284-C-T

Variant names:

• chr19-18880284-C-T
• rs925482243
• NM_021267.5:c.742G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021267.5(CERS1):​c.742G>A​(p.Gly248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000358 in 1,398,082 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: CERS1 NM_021267.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.772
• Publications: 0 publications found

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]

GDF1 Gene-Disease associations (from GenCC):

• right atrial isomerism

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, Ambry Genetics
• congenital heart defects, multiple types, 6

  Inheritance: AD Classification: LIMITED, NO_KNOWN Submitted by: Illumina, Ambry Genetics
• conotruncal heart malformations

  Inheritance: Unknown Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08621082).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021267.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	NM_021267.5	MANE Select	c.742G>A	p.Gly248Ser	missense	Exon 4 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-581G>A		5_prime_UTR	Exon 4 of 8	NP_001483.3
	CERS1	NM_001387439.1		c.742G>A	p.Gly248Ser	missense	Exon 4 of 7	NP_001374368.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.742G>A	p.Gly248Ser	missense	Exon 4 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.742G>A	p.Gly248Ser	missense	Exon 4 of 6	ENSP00000389044.1	P27544-2
	CERS1	ENST00000542296.6	TSL:1	c.448G>A	p.Gly150Ser	missense	Exon 4 of 6	ENSP00000437648.1	Q5XG75

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1398082 Hom.: 0 Cov.: 31 AF XY: 0.00000290 AC XY: 2 AN XY: 689622

African (AFR) AF: 0.00 AC: 0 AN: 31604

American (AMR) AF: 0.00 AC: 0 AN: 35750

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25096

East Asian (EAS) AF: 0.00 AC: 0 AN: 35806

South Asian (SAS) AF: 0.00 AC: 0 AN: 79056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49162

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4638

European-Non Finnish (NFE) AF: 0.00000463 AC: 5 AN: 1079028

Other (OTH) AF: 0.00 AC: 0 AN: 57942

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Progressive myoclonic epilepsy type 8 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	11
DANN	Benign	0.96
DEOGEN2	Uncertain	0.50	D
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.79	T
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.086	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.70	N
PhyloP100		0.77
PrimateAI	Benign	0.43	T
PROVEAN	Benign	0.95	N
REVEL	Benign	0.24
Sift	Benign	0.67	T
Sift4G	Benign	0.74	T
Polyphen		0.0020	B
Vest4		0.36
MutPred		0.51		Gain of MoRF binding (P = 0.1099)
MVP		0.28
ClinPred		0.10	T
GERP RS		-7.7
Varity_R		0.019
Mutation Taster		=85/15	polymorphism

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

Other links and lift over

dbSNP: rs925482243; hg19: chr19-18991093;