19-18868686-G-A
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Variant summary
Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM1BP4_Moderate
The NM_001492.6(GDF1):c.1030C>T(p.Pro344Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000166 in 1,564,532 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 Uncertain significance (★).
Frequency
Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000035 ( 0 hom. )
Consequence
GDF1
NM_001492.6 missense
NM_001492.6 missense
Scores
3
6
9
Clinical Significance
Conservation
PhyloP100: 3.89
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 Uncertain_significance. Variant got 0 ACMG points.
PM1
In a chain Embryonic growth/differentiation factor 1 (size 118) in uniprot entity GDF1_HUMAN there are 4 pathogenic changes around while only 1 benign (80%) in NM_001492.6
BP4
Computational evidence support a benign effect (MetaRNN=0.09747633).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GDF1 | NM_001492.6 | c.1030C>T | p.Pro344Ser | missense_variant | 8/8 | ENST00000247005.8 | NP_001483.3 | |
CERS1 | NM_021267.5 | c.*1299C>T | 3_prime_UTR_variant | 8/8 | ENST00000623882.4 | NP_067090.1 | ||
GDF1 | NM_001387438.1 | c.1030C>T | p.Pro344Ser | missense_variant | 5/5 | NP_001374367.1 | ||
CERS1 | NM_001387440.1 | c.*1891C>T | 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.1030C>T | p.Pro344Ser | missense_variant | 8/8 | 1 | NM_001492.6 | ENSP00000247005.5 | ||
CERS1 | ENST00000623882 | c.*1299C>T | 3_prime_UTR_variant | 8/8 | 1 | NM_021267.5 | ENSP00000485308.1 |
Frequencies
GnomAD3 genomes AF: 0.000138 AC: 21AN: 152012Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000354 AC: 5AN: 1412520Hom.: 0 Cov.: 31 AF XY: 0.00000286 AC XY: 2AN XY: 698376
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GnomAD4 genome AF: 0.000138 AC: 21AN: 152012Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9AN XY: 74264
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 01, 2021 | This sequence change replaces proline with serine at codon 344 of the GDF1 protein (p.Pro344Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals affected with GDF1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Uncertain
D;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N;.
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Benign
D;.
Sift4G
Uncertain
D;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
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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