NM_001492.6:c.925T>C

Variant names:

• chr19-18868791-A-G
• rs864622513
• NM_001492.6:c.925T>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_001492.6(GDF1):​c.925T>C​(p.Ser309Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000114 in 1,461,894 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S309F) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00011 (2 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:2
• Conservation: PhyloP100: 0.728
• Publications: 2 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: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035881877).
• BP6: Variant 19-18868791-A-G is Benign according to our data. Variant chr19-18868791-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 220404.
• BS2: High Homozygotes in GnomAdExome4 at 2 AD,AR,Unknown gene

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.925T>C	p.Ser309Pro	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*1194T>C		3_prime_UTR	Exon 8 of 8	NP_067090.1
	GDF1	NM_001387438.1		c.925T>C	p.Ser309Pro	missense	Exon 5 of 5	NP_001374367.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GDF1	ENST00000247005.8	TSL:1 MANE Select	c.925T>C	p.Ser309Pro	missense	Exon 8 of 8	ENSP00000247005.5
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*1194T>C		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1

Frequencies

GnomAD3 genomes AF: 0.000127 AC: 19 AN: 149084 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00113

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: 0.000975

GnomAD2 exomes AF: 0.00106 AC: 118 AN: 111764 AF XY: 0.000603

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00566

Gnomad ASJ exome AF: 0.000137

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000315

GnomAD4 exome AF: 0.000112 AC: 147 AN: 1312702 Hom.: 2 Cov.: 31 AF XY: 0.0000849 AC XY: 55 AN XY: 647564

African (AFR) AF: 0.00 AC: 0 AN: 25780

American (AMR) AF: 0.00464 AC: 142 AN: 30582

Ashkenazi Jewish (ASJ) AF: 0.0000463 AC: 1 AN: 21602

East Asian (EAS) AF: 0.00 AC: 0 AN: 26752

South Asian (SAS) AF: 0.00 AC: 0 AN: 75530

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 44946

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4534

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1030594

Other (OTH) AF: 0.0000764 AC: 4 AN: 52382

GnomAD4 genome AF: 0.000127 AC: 19 AN: 149192 Hom.: 0 Cov.: 33 AF XY: 0.0000686 AC XY: 5 AN XY: 72852

African (AFR) AF: 0.00 AC: 0 AN: 41182

American (AMR) AF: 0.00113 AC: 17 AN: 15048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3418

East Asian (EAS) AF: 0.00 AC: 0 AN: 5128

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 66882

Other (OTH) AF: 0.000964 AC: 2 AN: 2074

Alfa AF: 0.000131 Hom.: 0

Bravo AF: 0.000298

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	GDF1-related disorder (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.048
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	6.1
DANN	Benign	0.46
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.90
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.023	N
LIST_S2	Benign	0.29	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.036	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-0.46	N
PhyloP100		0.73
PROVEAN	Benign	-2.0	N
REVEL	Uncertain	0.53
Sift	Benign	0.25	T
Sift4G	Benign	0.31	T
Vest4		0.65
MutPred		0.80		Loss of catalytic residue at S309 (P = 0.0214)
MVP		0.47
MPC		1.2
ClinPred		0.021	T
GERP RS		0.87
Varity_R		0.18
gMVP		0.68
Mutation Taster		=86/14	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: rs864622513; hg19: chr19-18979600;