19-18869231-C-A

Variant names:

• chr19-18869231-C-A
• rs121434424
• NM_001492.6:c.485G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001492.6(GDF1):​c.485G>T​(p.Gly162Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000665 in 150,336 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G162D) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000067 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0550
• Publications: 5 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26075703).

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.485G>T	p.Gly162Val	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*754G>T		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.485G>T	p.Gly162Val	missense	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.485G>T	p.Gly162Val	missense	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*754G>T		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.00000665 AC: 1 AN: 150336 Hom.: 0 Cov.: 33

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1238690 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 606732

African (AFR) AF: 0.00 AC: 0 AN: 23808

American (AMR) AF: 0.00 AC: 0 AN: 13556

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17160

East Asian (EAS) AF: 0.00 AC: 0 AN: 26756

South Asian (SAS) AF: 0.00 AC: 0 AN: 58218

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29516

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3466

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1015628

Other (OTH) AF: 0.00 AC: 0 AN: 50582

GnomAD4 genome AF: 0.00000665 AC: 1 AN: 150336 Hom.: 0 Cov.: 33 AF XY: 0.0000136 AC XY: 1 AN XY: 73356

African (AFR) AF: 0.0000242 AC: 1 AN: 41256

American (AMR) AF: 0.00 AC: 0 AN: 15116

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 5148

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9856

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67404

Other (OTH) AF: 0.00 AC: 0 AN: 2060

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	19
DANN	Benign	0.97
DEOGEN2	Benign	0.12	T
Eigen	Benign	-0.50
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.42	T
M_CAP	Pathogenic	0.76	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		-0.055
PROVEAN	Benign	-0.46	N
REVEL	Benign	0.084
Sift	Benign	0.26	T
Sift4G	Benign	0.42	T
Vest4		0.14
MutPred		0.47		Gain of sheet (P = 0.0221)
MVP		0.21
MPC		2.2
ClinPred		0.45	T
GERP RS		2.1
Varity_R		0.082
gMVP		0.34
Mutation Taster		=82/18	polymorphism

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: rs121434424; hg19: chr19-18980040;