chr19-18868928-G-C

Variant names:

• chr19-18868928-G-C
• rs1555702266
• NM_001492.6:c.788C>G

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.788C>G​(p.Pro263Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000423 in 1,182,966 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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. P263L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000042 (0 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.336
• 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: 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=0.17884868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6	c.788C>G	p.Pro263Arg	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3
CERS1	NM_021267.5	c.*1057C>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1
GDF1	NM_001387438.1	c.788C>G	p.Pro263Arg	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1	c.*1649C>G		3_prime_UTR_variant	Exon 7 of 7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8	c.788C>G	p.Pro263Arg	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5
CERS1	ENST00000623882.4	c.*1057C>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000423 AC: 5 AN: 1182966 Hom.: 0 Cov.: 30 AF XY: 0.00000514 AC XY: 3 AN XY: 583386

African (AFR) AF: 0.00 AC: 0 AN: 21932

American (AMR) AF: 0.00 AC: 0 AN: 17782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17220

East Asian (EAS) AF: 0.00 AC: 0 AN: 18124

South Asian (SAS) AF: 0.00 AC: 0 AN: 65532

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 28490

Middle Eastern (MID) AF: 0.000315 AC: 1 AN: 3170

European-Non Finnish (NFE) AF: 0.00000311 AC: 3 AN: 965252

Other (OTH) AF: 0.0000220 AC: 1 AN: 45464

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.92
DEOGEN2	Uncertain	0.46	T;.
Eigen	Benign	-0.71
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.39	N
LIST_S2	Benign	0.37	T;.
M_CAP	Pathogenic	0.53	D
MetaRNN	Benign	0.18	T;T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	1.0	L;.
PhyloP100		0.34
PROVEAN	Uncertain	-3.2	D;.
REVEL	Benign	0.21
Sift	Benign	0.065	T;.
Sift4G	Benign	0.068	T;T
Vest4		0.058
MutPred		0.45		Gain of MoRF binding (P = 6e-04);Gain of MoRF binding (P = 6e-04);
MVP		0.15
MPC		1.4
ClinPred		0.13	T
GERP RS		-0.48
Varity_R		0.060
gMVP		0.13
Mutation Taster		=89/11	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: rs1555702266; hg19: chr19-18979737;