rs4808870

Positions:

• chr19-18878511-T-C
• chr19-18878511-T-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000429504.6(CERS1):​c.*415A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.894 in 1,011,886 control chromosomes in the GnomAD database, including 404,873 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (63081 hom., cov: 30)
  • Exomes 𝑓: 0.89 (341792 hom.)
• Consequence: CERS1 ENST00000429504.6 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.50

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.93).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.96 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF1	NM_001492.6	c.-313+419A>G		intron_variant		ENST00000247005.8
CERS1	NM_021267.5	c.1010+419A>G		intron_variant		ENST00000623882.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8	c.-313+419A>G		intron_variant		1	NM_001492.6	P1
CERS1	ENST00000623882.4	c.1010+419A>G		intron_variant		1	NM_021267.5	P2

Frequencies

GnomAD3 genomes AF: 0.909 AC: 138252 AN: 152036 Hom.: 63019 Cov.: 30

Gnomad AFR AF: 0.968

Gnomad AMI AF: 0.874

Gnomad AMR AF: 0.920

Gnomad ASJ AF: 0.934

Gnomad EAS AF: 0.775

Gnomad SAS AF: 0.858

Gnomad FIN AF: 0.874

Gnomad MID AF: 0.896

Gnomad NFE AF: 0.889

Gnomad OTH AF: 0.922

GnomAD4 exome AF: 0.891 AC: 766332 AN: 859732 Hom.: 341792 Cov.: 56 AF XY: 0.891 AC XY: 355624 AN XY: 399124

Gnomad4 AFR exome AF: 0.971

Gnomad4 AMR exome AF: 0.925

Gnomad4 ASJ exome AF: 0.933

Gnomad4 EAS exome AF: 0.774

Gnomad4 SAS exome AF: 0.852

Gnomad4 FIN exome AF: 0.892

Gnomad4 NFE exome AF: 0.891

Gnomad4 OTH exome AF: 0.882

GnomAD4 genome AF: 0.909 AC: 138375 AN: 152154 Hom.: 63081 Cov.: 30 AF XY: 0.907 AC XY: 67426 AN XY: 74368

Gnomad4 AFR AF: 0.968

Gnomad4 AMR AF: 0.920

Gnomad4 ASJ AF: 0.934

Gnomad4 EAS AF: 0.776

Gnomad4 SAS AF: 0.858

Gnomad4 FIN AF: 0.874

Gnomad4 NFE AF: 0.889

Gnomad4 OTH AF: 0.922

Alfa AF: 0.902 Hom.: 13441

Bravo AF: 0.917

Asia WGS AF: 0.840 AC: 2922 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.11
DANN	Benign	0.23

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: rs4808870; hg19: chr19-18989320;