rs374016704

Variant names:

• chr19-18868625-A-G
• rs374016704
• NM_001492.6:c.1091T>C
• GDF1 p.Met364Thr

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 11P and 1B. PM5 PP3 PP5_Very_Strong BP4

The NM_001492.6(GDF1):​c.1091T>C​(p.Met364Thr) variant causes a missense change. The variant allele was found at a frequency of 0.000209 in 1,571,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M364I) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (0 hom.)
• Consequence: GDF1 NM_001492.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9
• Conservation: PhyloP100: 7.14
• Publications: 7 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)
• progressive myoclonus epilepsy

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-18868624-C-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1507891.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, Cadd, M_CAP, MutationAssessor, PROVEAN, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• PP5: Variant 19-18868625-A-G is Pathogenic according to our data. Variant chr19-18868625-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 522571.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.0835813). . Strength limited to SUPPORTING due to the PP5.

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.1091T>C	p.Met364Thr	missense	Exon 8 of 8	NP_001483.3
	CERS1	NM_021267.5	MANE Select	c.*1360T>C		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
	GDF1	NM_001387438.1		c.1091T>C	p.Met364Thr	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.1091T>C	p.Met364Thr	missense	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*1360T>C		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152086 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.000508 AC: 93 AN: 182990 AF XY: 0.000526

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000708

Gnomad ASJ exome AF: 0.00889

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000105

Gnomad OTH exome AF: 0.00104

GnomAD4 exome AF: 0.000202 AC: 287 AN: 1419596 Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 149 AN XY: 702218

African (AFR) AF: 0.00 AC: 0 AN: 32594

American (AMR) AF: 0.0000512 AC: 2 AN: 39040

Ashkenazi Jewish (ASJ) AF: 0.00771 AC: 195 AN: 25286

East Asian (EAS) AF: 0.00 AC: 0 AN: 37500

South Asian (SAS) AF: 0.00 AC: 0 AN: 80780

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49176

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5714

European-Non Finnish (NFE) AF: 0.0000367 AC: 40 AN: 1090836

Other (OTH) AF: 0.000852 AC: 50 AN: 58670

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152086 Hom.: 0 Cov.: 33 AF XY: 0.000310 AC XY: 23 AN XY: 74296

African (AFR) AF: 0.0000241 AC: 1 AN: 41424

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.0101 AC: 35 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67982

Other (OTH) AF: 0.000479 AC: 1 AN: 2088

Alfa AF: 0.00101 Hom.: 0

Bravo AF: 0.000306

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	-	-	not provided (4)
1	-	-	Congenital heart defects, multiple types (1)
1	-	-	Congenital heart defects, multiple types, 6 (1)
1	-	-	Congenital heart defects, multiple types, 6;C3178806:Right atrial isomerism (1)
1	-	-	Heart, malformation of (1)
1	-	-	Right atrial isomerism (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.087	D
BayesDel_noAF	Uncertain	0.11
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.97	D
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.52
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.95	D
M_CAP	Pathogenic	0.86	D
MetaRNN	Benign	0.084	T
MetaSVM	Pathogenic	0.86	D
MutationAssessor	Pathogenic	3.3	M
PhyloP100		7.1
PROVEAN	Pathogenic	-5.6	D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Varity_R		0.90
gMVP		0.93
Mutation Taster		=20/80	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374016704;

hg19: chr19-18979434;