NM_001492.6:c.800G>A

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PP3_Strong

The NM_001492.6(GDF1):c.800G>A(p.Cys267Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000585 in 1,367,468 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000068 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000057 ( 0 hom. )

Consequence

GDF1
NM_001492.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter P:1U:1

Conservation

PhyloP100: 2.07

Publications

5 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: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae)

CERS1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GDF1	NM_001492.6 link	c.800G>A	p.Cys267Tyr	missense_variant	Exon 8 of 8	ENST00000247005.8	NP_001483.3	P27539A0A024R7N8
CERS1	NM_021267.5 link	c.*1069G>A		3_prime_UTR_variant	Exon 8 of 8	ENST00000623882.4	NP_067090.1	P27544-1
GDF1	NM_001387438.1 link	c.800G>A	p.Cys267Tyr	missense_variant	Exon 5 of 5		NP_001374367.1
CERS1	NM_001387440.1 link	c.*1661G>A		3_prime_UTR_variant	Exon 7 of 7		NP_001374369.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GDF1	ENST00000247005.8 link	c.800G>A	p.Cys267Tyr	missense_variant	Exon 8 of 8	1	NM_001492.6	ENSP00000247005.5		P27539
CERS1	ENST00000623882.4 link	c.*1069G>A		3_prime_UTR_variant	Exon 8 of 8	1	NM_021267.5	ENSP00000485308.1		P27544-1

Frequencies

GnomAD3 genomes

AF:

0.00000676

AC:

AN:

147840

Hom.:

Cov.:

show subpopulations

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:

0.0000151

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

73392

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000574

AC:

AN:

1219628

Hom.:

Cov.:

AF XY:

0.00000332

AC XY:

AN XY:

601998

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

22910

American (AMR)

AF:

0.00

AC:

AN:

22842

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

18694

East Asian (EAS)

AF:

0.00

AC:

AN:

19446

South Asian (SAS)

AF:

0.00

AC:

AN:

70612

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29720

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3354

European-Non Finnish (NFE)

AF:

0.00000711

AC:

AN:

984648

Other (OTH)

AF:

0.00

AC:

AN:

47402

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.646

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000676

AC:

AN:

147840

Hom.:

Cov.:

AF XY:

0.0000139

AC XY:

AN XY:

72008

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41036

American (AMR)

AF:

0.00

AC:

AN:

14878

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3400

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

8928

Middle Eastern (MID)

AF:

0.00

AC:

AN:

314

European-Non Finnish (NFE)

AF:

0.0000151

AC:

AN:

66340

Other (OTH)

AF:

0.00

AC:

AN:

2036

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

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

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Double outlet right ventricle

Pathogenic:1

Nov 01, 2007

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

GDF1-related disorder

Uncertain:1

Aug 23, 2022

PreventionGenetics, part of Exact Sciences

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The GDF1 c.800G>A variant is predicted to result in the amino acid substitution p.Cys267Tyr. This variant was reported in an individual with double outlet right ventricle and pulmonary artery stenosis (Karkera et al. 2007. PubMed ID: 17924340). Studies in zebrafish found the variant may impact protein function; however, the biological significance of this data is unclear (Karkera et al. 2007. PubMed ID: 17924340). This variant is reported in 0.017% of alleles in individuals of European (Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/19-18979725-C-T). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.43

BayesDel_noAF

Pathogenic

0.38

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.97

D;.

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Benign

0.65

LIST_S2

Benign

0.56

T;.

M_CAP

Pathogenic

0.80

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.7

H;.

PhyloP100

2.1

PROVEAN

Pathogenic

-9.7

D;.

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Vest4

0.93

MutPred

0.98

Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);

MVP

0.78

MPC

2.6

ClinPred

1.0

GERP RS

3.3

Varity_R

0.95

gMVP

0.69

Mutation Taster

=34/66

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over