rs571387097

Variant names:

• chr19-18869245-TGCCGCCGCC-T
• rs571387097
• NM_001492.6:c.462_470delGGCGGCGGC

Your query was ambiguous. Multiple possible variants found:

• chr19-18869245-TGCCGCCGCC-T
• chr19-18869245-TGCCGCCGCC-TGCC
• chr19-18869245-TGCCGCCGCC-TGCCGCC
• chr19-18869245-TGCCGCCGCC-TGCCGCCGCCGCC
• chr19-18869245-TGCCGCCGCC-TGCCGCCGCCGCCGCC
• chr19-18869245-TGCCGCCGCC-TGCCGCCGCCGCCGCCGCC
• chr19-18869245-TGCCGCCGCC-TGCCGCCGCCGCCGCCGCCGCC

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP3

The NM_001492.6(GDF1):​c.462_470delGGCGGCGGC​(p.Ala155_Ala157del) variant causes a disruptive inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000231 in 1,428,202 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: GDF1 NM_001492.6 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.58
• Publications: 6 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
• progressive myoclonus epilepsy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001492.6

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001492.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	NM_001492.6	MANE Select	c.462_470delGGCGGCGGC	p.Ala155_Ala157del	disruptive_inframe_deletion	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*731_*739delGGCGGCGGC		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.462_470delGGCGGCGGC	p.Ala155_Ala157del	disruptive_inframe_deletion	Exon 5 of 5	NP_001374367.1	P27539

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.462_470delGGCGGCGGC	p.Ala155_Ala157del	disruptive_inframe_deletion	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*731_*739delGGCGGCGGC		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150516 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000960 AC: 3 AN: 31234 AF XY: 0.0000541

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000291

Gnomad ASJ exome AF: 0.000446

Gnomad EAS 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: 0.0000243 AC: 31 AN: 1277686 Hom.: 0 AF XY: 0.0000223 AC XY: 14 AN XY: 627910

African (AFR) AF: 0.0000401 AC: 1 AN: 24920

American (AMR) AF: 0.000104 AC: 2 AN: 19272

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19612

East Asian (EAS) AF: 0.00 AC: 0 AN: 28020

South Asian (SAS) AF: 0.0000312 AC: 2 AN: 64146

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3654

European-Non Finnish (NFE) AF: 0.0000242 AC: 25 AN: 1034548

Other (OTH) AF: 0.0000190 AC: 1 AN: 52696

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150516 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73502

African (AFR) AF: 0.0000242 AC: 1 AN: 41266

American (AMR) AF: 0.00 AC: 0 AN: 15150

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3442

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9982

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67398

Other (OTH) AF: 0.00 AC: 0 AN: 2068

Alfa AF: 0.00 Hom.: 17

Bravo AF: 0.0000340

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.6
Mutation Taster		=162/38	polymorphism

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs571387097; hg19: chr19-18980054;