chr19-18895839-A-C

Variant names:

• chr19-18895839-A-C
• rs113536478
• NM_021267.5:c.234T>G

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_021267.5(CERS1):​c.234T>G​(p.Thr78Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000884 in 1,131,446 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. T78T) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 8.8e-7 (0 hom.)
• Consequence: CERS1 NM_021267.5 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.282
• 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: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP7: Synonymous conserved (PhyloP=0.282 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CERS1	NM_021267.5	c.234T>G	p.Thr78Thr	synonymous_variant	Exon 1 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001492.6	c.-1089T>G		5_prime_UTR_variant	Exon 1 of 8	ENST00000247005.8	NP_001483.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CERS1	ENST00000623882.4	c.234T>G	p.Thr78Thr	synonymous_variant	Exon 1 of 8	1	NM_021267.5	ENSP00000485308.1
CERS1	ENST00000429504.6	c.234T>G	p.Thr78Thr	synonymous_variant	Exon 1 of 6	1		ENSP00000389044.1
GDF1	ENST00000247005.8	c.-1089T>G		5_prime_UTR_variant	Exon 1 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000542296.6	c.-46+722T>G		intron_variant	Intron 1 of 5	1		ENSP00000437648.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 8.84e-7 AC: 1 AN: 1131446 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 549566

⚠️ 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: 21324

American (AMR) AF: 0.00 AC: 0 AN: 8910

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14482

East Asian (EAS) AF: 0.00 AC: 0 AN: 23490

South Asian (SAS) AF: 0.00 AC: 0 AN: 45156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 25048

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2906

European-Non Finnish (NFE) AF: 0.00000106 AC: 1 AN: 945970

Other (OTH) AF: 0.00 AC: 0 AN: 44160

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	13
DANN	Benign	0.71
PhyloP100		0.28
PromoterAI		0.042	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.6

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: rs113536478; hg19: chr19-19006648;