rs121434423
Positions:
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PP3_Strong
The ENST00000247005.8(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
ENST00000247005.8 missense
ENST00000247005.8 missense
Scores
12
3
3
Clinical Significance
Conservation
PhyloP100: 2.07
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]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM1
In a disulfide_bond (size 70) in uniprot entity GDF1_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in ENST00000247005.8
PP3
MetaRNN computational evidence supports a deleterious effect, 0.993
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GDF1 | NM_001492.6 | c.800G>A | p.Cys267Tyr | missense_variant | 8/8 | ENST00000247005.8 | NP_001483.3 | |
CERS1 | NM_021267.5 | c.*1069G>A | 3_prime_UTR_variant | 8/8 | ENST00000623882.4 | NP_067090.1 | ||
GDF1 | NM_001387438.1 | c.800G>A | p.Cys267Tyr | missense_variant | 5/5 | NP_001374367.1 | ||
CERS1 | NM_001387440.1 | c.*1661G>A | 3_prime_UTR_variant | 7/7 | NP_001374369.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GDF1 | ENST00000247005.8 | c.800G>A | p.Cys267Tyr | missense_variant | 8/8 | 1 | NM_001492.6 | ENSP00000247005 | P1 | |
CERS1 | ENST00000623882.4 | c.*1069G>A | 3_prime_UTR_variant | 8/8 | 1 | NM_021267.5 | ENSP00000485308 | P2 |
Frequencies
GnomAD3 genomes AF: 0.00000676 AC: 1AN: 147840Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000574 AC: 7AN: 1219628Hom.: 0 Cov.: 30 AF XY: 0.00000332 AC XY: 2AN XY: 601998
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GnomAD4 genome AF: 0.00000676 AC: 1AN: 147840Hom.: 0 Cov.: 33 AF XY: 0.0000139 AC XY: 1AN XY: 72008
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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
Pathogenic, no assertion criteria provided | literature only | OMIM | Nov 01, 2007 | - - |
GDF1-related disorder Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Aug 23, 2022 | 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:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Benign
T;.
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
H;.
MutationTaster
Benign
A;A
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Vest4
MutPred
Loss of sheet (P = 0.0315);Loss of sheet (P = 0.0315);
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at