rs1232905914

chr19-18868666-AAAG-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM1 PM4_Supporting

The NM_001492.6(GDF1):c.1047_1049del(p.Phe350del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.00000562 in 1,422,498 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000056 (0 hom.)
• Consequence: GDF1 NM_001492.6 inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 3.76

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 7 pathogenic changes around while only 2 benign (78%) in NM_001492.6
• PM4: Nonframeshift variant in NON repetitive region in NM_001492.6. Strenght limited to Supporting due to length of the change: 1aa.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GDF1	NM_001492.6	c.1047_1049del	p.Phe350del	inframe_deletion	8/8	ENST00000247005.8
CERS1	NM_021267.5	c.*1316_*1318del		3_prime_UTR_variant	8/8	ENST00000623882.4
GDF1	NM_001387438.1	c.1047_1049del	p.Phe350del	inframe_deletion	5/5
CERS1	NM_001387440.1	c.*1908_*1910del		3_prime_UTR_variant	7/7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GDF1	ENST00000247005.8	c.1047_1049del	p.Phe350del	inframe_deletion	8/8	1	NM_001492.6	P1
CERS1	ENST00000623882.4	c.*1316_*1318del		3_prime_UTR_variant	8/8	1	NM_021267.5	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000541 AC: 1 AN: 184904 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 99940

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000353

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000562 AC: 8 AN: 1422498 Hom.: 0 AF XY: 0.00000568 AC XY: 4 AN XY: 703910

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000508

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000264

Gnomad4 SAS exome AF: 0.0000123

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000366

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Visceral heterotaxy Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jul 21, 2017

This sequence change deletes 3 nucleotides from exon 8 of the GDF1 mRNA (c.1047_1049delCTT). This leads to the deletion of 1 amino acid residue in the GDF1 protein (p.Phe350del) but otherwise preserves the integrity of the reading frame. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a GDF1-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, this is a rare in-frame deletion with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance. -

Progressive myoclonic epilepsy type 8 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

- -

Computational scores

Source: dbNSFP v4.3

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: rs1232905914; hg19: chr19-18979475;