chr19-18869245-TGCC-T

Position:

• chr19-18869245-TGCC-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP3 BP6

The NM_001492.6(GDF1):​c.468_470delGGC​(p.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 0.000219 in 1,421,404 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in Lovd as Benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00024 (0 hom.)
• Consequence: GDF1 NM_001492.6 disruptive_inframe_deletion
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.179

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 Likely_benign. Variant got -2 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001492.6
• BP6: Variant 19-18869245-TGCC-T is Benign according to our data. Variant chr19-18869245-TGCC-T is described in Lovd as [Benign]. Variant chr19-18869245-TGCC-T is described in Lovd as [Likely_benign]. Variant chr19-18869245-TGCC-T is described in Lovd as [Benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GDF1	NM_001492.6	c.468_470delGGC	p.Ala157del	disruptive_inframe_deletion	8/8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*737_*739delGGC		3_prime_UTR_variant	8/8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.468_470delGGC	p.Ala157del	disruptive_inframe_deletion	5/5		NP_001374367.1
CERS1	NM_001387440.1	c.*1329_*1331delGGC		3_prime_UTR_variant	7/7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.468_470delGGC	p.Ala157del	disruptive_inframe_deletion	8/8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882	c.*737_*739delGGC		3_prime_UTR_variant	8/8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.0000133 AC: 2 AN: 150506 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

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: 0.0000297

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.000243 AC: 309 AN: 1270898 Hom.: 0 AF XY: 0.000250 AC XY: 156 AN XY: 624300

Gnomad4 AFR exome AF: 0.000444

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.000411

Gnomad4 EAS exome AF: 0.000323

Gnomad4 SAS exome AF: 0.000888

Gnomad4 FIN exome AF: 0.000295

Gnomad4 NFE exome AF: 0.000168

Gnomad4 OTH exome AF: 0.000325

GnomAD4 genome AF: 0.0000133 AC: 2 AN: 150506 Hom.: 0 Cov.: 32 AF XY: 0.0000136 AC XY: 1 AN XY: 73498

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000297

Gnomad4 OTH AF: 0.00

ClinVar

Not reported in ClinVar

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: rs571387097; hg19: chr19-18980054;