chr19-18868694-C-T

Variant names:

• chr19-18868694-C-T
• rs1446194780
• NM_001492.6:c.1022G>A

Variant summary

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

The NM_001492.6(GDF1):​c.1022G>A​(p.Arg341His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000449 in 1,557,398 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000043 (0 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.06
• 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: 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.

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.1022G>A	p.Arg341His	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*1291G>A		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.1022G>A	p.Arg341His	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.1022G>A	p.Arg341His	missense	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*1291G>A		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 33

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000427 AC: 6 AN: 1405482 Hom.: 0 Cov.: 31 AF XY: 0.00000288 AC XY: 2 AN XY: 694350

African (AFR) AF: 0.00 AC: 0 AN: 32072

American (AMR) AF: 0.0000270 AC: 1 AN: 37024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25038

East Asian (EAS) AF: 0.00 AC: 0 AN: 36528

South Asian (SAS) AF: 0.00 AC: 0 AN: 79996

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 48412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5640

European-Non Finnish (NFE) AF: 0.00000462 AC: 5 AN: 1082620

Other (OTH) AF: 0.00 AC: 0 AN: 58152

GnomAD4 genome AF: 0.00000658 AC: 1 AN: 151916 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74224

African (AFR) AF: 0.00 AC: 0 AN: 41406

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10476

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67962

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Benign	0.0020	T
BayesDel_noAF	Benign	-0.23
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	D
Eigen	Benign	-0.019
Eigen_PC	Benign	-0.086
FATHMM_MKL	Benign	0.23	N
LIST_S2	Pathogenic	0.99	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.1	M
PhyloP100		1.1
PROVEAN	Uncertain	-3.3	D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.0080	D
Vest4		0.33
MVP		0.45
MPC		2.3
ClinPred		0.96	D
GERP RS		2.4
Varity_R		0.19
gMVP		0.76
Mutation Taster		=93/7	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: rs1446194780; hg19: chr19-18979503;