chr19-18868804-G-A

Variant names:

• chr19-18868804-G-A
• rs551588378
• NM_001492.6:c.912C>T

Variant summary

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

The ENST00000247005.8(GDF1):​c.912C>T​(p.Val304Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000765 in 1,306,960 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. V304V) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.7e-7 (0 hom.)
• Consequence: GDF1 ENST00000247005.8 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288
• Publications: 0 publications found

Genes affected

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]

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]

CERS1 Gene-Disease associations (from GenCC):

• progressive myoclonic epilepsy type 8

  Inheritance: AR Classification: STRONG, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Orphanet, 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=-0.78).
• BP7: Synonymous conserved (PhyloP=-0.288 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000247005.8. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.912C>T	p.Val304Val	synonymous	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*1181C>T		3_prime_UTR	Exon 8 of 8	NP_067090.1
	GDF1	NM_001387438.1		c.912C>T	p.Val304Val	synonymous	Exon 5 of 5	NP_001374367.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.912C>T	p.Val304Val	synonymous	Exon 8 of 8	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*1181C>T		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.65e-7 AC: 1 AN: 1306960 Hom.: 0 Cov.: 31 AF XY: 0.00000155 AC XY: 1 AN XY: 645072

African (AFR) AF: 0.00 AC: 0 AN: 25786

American (AMR) AF: 0.00 AC: 0 AN: 30840

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21374

East Asian (EAS) AF: 0.00 AC: 0 AN: 26462

South Asian (SAS) AF: 0.00 AC: 0 AN: 75770

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43194

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4480

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1027124

Other (OTH) AF: 0.0000193 AC: 1 AN: 51930

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.7
DANN	Benign	0.88
PhyloP100		-0.29

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs551588378; hg19: chr19-18979613; COSMIC: COSV53200733; COSMIC: COSV53200733;