rs4808863

Variant names:

• chr19-18869363-G-A
• rs4808863
• NM_001492.6:c.353C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001492.6(GDF1):​c.353C>T​(p.Ala118Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.372 in 1,530,440 control chromosomes in the GnomAD database, including 111,915 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A118A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.30 (8791 hom., cov: 32)
  • Exomes 𝑓: 0.38 (103124 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.0450
• Publications: 23 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=1.7131752E-5).
• BP6: Variant 19-18869363-G-A is Benign according to our data. Variant chr19-18869363-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 258160.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.461 is higher than 0.05.

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.353C>T	p.Ala118Val	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*622C>T		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.353C>T	p.Ala118Val	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.353C>T	p.Ala118Val	missense	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*622C>T		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.304 AC: 46097 AN: 151626 Hom.: 8785 Cov.: 32

Gnomad AFR AF: 0.0865

Gnomad AMI AF: 0.308

Gnomad AMR AF: 0.469

Gnomad ASJ AF: 0.535

Gnomad EAS AF: 0.181

Gnomad SAS AF: 0.241

Gnomad FIN AF: 0.325

Gnomad MID AF: 0.442

Gnomad NFE AF: 0.396

Gnomad OTH AF: 0.354

GnomAD2 exomes AF: 0.372 AC: 47398 AN: 127342 AF XY: 0.362

Gnomad AFR exome AF: 0.0750

Gnomad AMR exome AF: 0.527

Gnomad ASJ exome AF: 0.531

Gnomad EAS exome AF: 0.186

Gnomad FIN exome AF: 0.338

Gnomad NFE exome AF: 0.403

Gnomad OTH exome AF: 0.421

GnomAD4 exome AF: 0.379 AC: 522459 AN: 1378704 Hom.: 103124 Cov.: 38 AF XY: 0.375 AC XY: 255528 AN XY: 680706

African (AFR) AF: 0.0724 AC: 2240 AN: 30932

American (AMR) AF: 0.522 AC: 18620 AN: 35670

Ashkenazi Jewish (ASJ) AF: 0.534 AC: 13304 AN: 24910

East Asian (EAS) AF: 0.218 AC: 7664 AN: 35150

South Asian (SAS) AF: 0.241 AC: 19069 AN: 79070

European-Finnish (FIN) AF: 0.347 AC: 11605 AN: 33488

Middle Eastern (MID) AF: 0.453 AC: 1835 AN: 4054

European-Non Finnish (NFE) AF: 0.396 AC: 427166 AN: 1077886

Other (OTH) AF: 0.364 AC: 20956 AN: 57544

GnomAD4 genome AF: 0.304 AC: 46105 AN: 151736 Hom.: 8791 Cov.: 32 AF XY: 0.302 AC XY: 22425 AN XY: 74170

African (AFR) AF: 0.0864 AC: 3584 AN: 41486

American (AMR) AF: 0.470 AC: 7173 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.535 AC: 1849 AN: 3454

East Asian (EAS) AF: 0.181 AC: 926 AN: 5126

South Asian (SAS) AF: 0.241 AC: 1159 AN: 4816

European-Finnish (FIN) AF: 0.325 AC: 3416 AN: 10520

Middle Eastern (MID) AF: 0.455 AC: 132 AN: 290

European-Non Finnish (NFE) AF: 0.396 AC: 26850 AN: 67756

Other (OTH) AF: 0.349 AC: 737 AN: 2110

Alfa AF: 0.380 Hom.: 15464

Bravo AF: 0.310

TwinsUK AF: 0.401 AC: 1486

ALSPAC AF: 0.406 AC: 1566

ExAC AF: 0.247 AC: 20016

Asia WGS AF: 0.207 AC: 715 AN: 3456

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not specified (7)
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	6.7
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.92
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.090	N
LIST_S2	Benign	0.43	T
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.045
PROVEAN	Benign	-0.52	N
REVEL	Benign	0.11
Sift	Benign	0.52	T
Sift4G	Benign	0.34	T
Vest4		0.0090
MPC		0.95
ClinPred		0.0025	T
GERP RS		0.93
Varity_R		0.031
gMVP		0.17
Mutation Taster		=97/3	polymorphism (auto)

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: rs4808863; hg19: chr19-18980172; COSMIC: COSV53200920; COSMIC: COSV53200920;