rs121434422

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1_StrongPP5_Very_Strong

The NM_001492.6(GDF1):c.681C>A(p.Cys227*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000943 in 1,073,414 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.00054 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0010 ( 0 hom. )

Consequence

GDF1
NM_001492.6 stop_gained

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16

Conservation

PhyloP100: -0.0420

Publications

7 publications found

Variant links:

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]

GDF1 links:

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

CERS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 12 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.

PP5

Variant 19-18869035-G-T is Pathogenic according to our data. Variant chr19-18869035-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 6747.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GDF1	NM_001492.6	MANE Select	c.681C>A	p.Cys227*	stop_gained	Exon 8 of 8	NP_001483.3
CERS1	NM_021267.5	MANE Select	c.*950C>A		3_prime_UTR	Exon 8 of 8	NP_067090.1	P27544-1
GDF1	NM_001387438.1		c.681C>A	p.Cys227*	stop_gained	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.681C>A	p.Cys227*	stop_gained	Exon 8 of 8	ENSP00000247005.5	P27539
	CERS1	ENST00000623882.4	TSL:1 MANE Select	c.*950C>A		3_prime_UTR	Exon 8 of 8	ENSP00000485308.1	P27544-1

Frequencies

GnomAD3 genomes

AF:

0.000536

AC:

AN:

147314

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000146

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:

0.000918

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000967

Gnomad OTH

AF:

0.000492

GnomAD2 exomes

AF:

0.00

AC:

AN:

306

AF XY:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00101

AC:

933

AN:

926100

Hom.:

Cov.:

AF XY:

0.000995

AC XY:

433

AN XY:

435070

show subpopulations

African (AFR)

AF:

0.000172

AC:

AN:

17472

American (AMR)

AF:

0.00

AC:

AN:

3626

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

7656

East Asian (EAS)

AF:

0.00

AC:

AN:

10490

South Asian (SAS)

AF:

0.00

AC:

AN:

18334

European-Finnish (FIN)

AF:

0.00173

AC:

AN:

12150

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2080

European-Non Finnish (NFE)

AF:

0.00108

AC:

887

AN:

821586

Other (OTH)

AF:

0.000673

AC:

AN:

32706

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

108

161

215

269

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000536

AC:

AN:

147314

Hom.:

Cov.:

AF XY:

0.000544

AC XY:

AN XY:

71724

show subpopulations

African (AFR)

AF:

0.000146

AC:

AN:

40986

American (AMR)

AF:

0.00

AC:

AN:

14830

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3390

East Asian (EAS)

AF:

0.00

AC:

AN:

5150

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000918

AC:

AN:

8712

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.000967

AC:

AN:

66158

Other (OTH)

AF:

0.000492

AC:

AN:

2032

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.511

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00115

Hom.:

Bravo

AF:

0.000465

ClinVar

ClinVar submissions

Significance:Pathogenic/Likely pathogenic

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Right atrial isomerism (5)

not provided (4)

Congenital heart defects, multiple types, 6;C3178806:Right atrial isomerism (3)

Congenital heart defects, multiple types, 6 (1)

GDF1-related disorder (1)

GDF1-RELATED DISORDERS (1)

Transposition of the great arteries (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.28

BayesDel_noAF

Uncertain

0.11

CADD

Pathogenic

(source)

DANN

Benign

0.96

Eigen

Benign

-0.67

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.024

PhyloP100

-0.042

Vest4

0.57

GERP RS

-2.4

Mutation Taster

=51/149

disease causing (ClinVar)

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over