19-18878511-T-C

Variant names:

• chr19-18878511-T-C
• rs4808870
• ENST00000429504.6:c.*415A>G

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.-313+419A>G		intron_variant	Intron 6 of 7	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.1010+419A>G		intron_variant	Intron 6 of 7	ENST00000623882.4	NP_067090.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.-313+419A>G		intron_variant	Intron 6 of 7	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.1010+419A>G		intron_variant	Intron 6 of 7	1	NM_021267.5	ENSP00000485308.1

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

African (AFR) AF: 0.971 AC: 15920 AN: 16396

American (AMR) AF: 0.925 AC: 3411 AN: 3688

Ashkenazi Jewish (ASJ) AF: 0.933 AC: 5353 AN: 5740

East Asian (EAS) AF: 0.774 AC: 3691 AN: 4766

South Asian (SAS) AF: 0.852 AC: 17411 AN: 20424

European-Finnish (FIN) AF: 0.892 AC: 1131 AN: 1268

Middle Eastern (MID) AF: 0.892 AC: 1507 AN: 1690

European-Non Finnish (NFE) AF: 0.891 AC: 692670 AN: 777138

Other (OTH) AF: 0.882 AC: 25238 AN: 28622

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

African (AFR) AF: 0.968 AC: 40192 AN: 41526

American (AMR) AF: 0.920 AC: 14067 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 3244 AN: 3472

East Asian (EAS) AF: 0.776 AC: 3994 AN: 5150

South Asian (SAS) AF: 0.858 AC: 4136 AN: 4822

European-Finnish (FIN) AF: 0.874 AC: 9268 AN: 10602

Middle Eastern (MID) AF: 0.908 AC: 267 AN: 294

European-Non Finnish (NFE) AF: 0.889 AC: 60466 AN: 67984

Other (OTH) AF: 0.922 AC: 1944 AN: 2108

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
PhyloP100		-1.5
Mutation Taster		=100/0	polymorphism (auto)

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: rs4808870; hg19: chr19-18989320;