19-18884118-G-A

Variant names:

• chr19-18884118-G-A
• rs772627907
• NM_021267.5:c.559C>T

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L187V) has been classified as Uncertain significance.

• 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
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.559C>T	p.Leu187Phe	missense	Exon 3 of 8	NP_067090.1	P27544-1
	GDF1	NM_001492.6	MANE Select	c.-764C>T		5_prime_UTR	Exon 3 of 8	NP_001483.3
	CERS1	NM_001387439.1		c.559C>T	p.Leu187Phe	missense	Exon 3 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.559C>T	p.Leu187Phe	missense	Exon 3 of 8	ENSP00000485308.1	P27544-1
	CERS1	ENST00000429504.6	TSL:1	c.559C>T	p.Leu187Phe	missense	Exon 3 of 6	ENSP00000389044.1	P27544-2
	CERS1	ENST00000542296.6	TSL:1	c.265C>T	p.Leu89Phe	missense	Exon 3 of 6	ENSP00000437648.1	Q5XG75

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245662 AF XY: 0.00

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 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

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86184

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111790

Other (OTH) AF: 0.00 AC: 0 AN: 60368

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000203476), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000825 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.64	D
LIST_S2	Benign	0.82	T
M_CAP	Benign	0.084	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.32	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		2.0
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.48
Sift	Benign	0.14	T
Sift4G	Benign	0.39	T
Polyphen		0.73	P
Vest4		0.55
MutPred		0.67		Loss of catalytic residue at T186 (P = 0.3817)
MVP		0.56
ClinPred		0.48	T
GERP RS		-0.52
PromoterAI		-0.014	Neutral
Varity_R		0.16
Mutation Taster		=77/23	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: rs772627907; hg19: chr19-18994927;