rs374016704
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Variant summary
Our verdict is Pathogenic. Variant got 10 ACMG points: 11P and 1B. PM1PP3PP5_Very_StrongBP4
The NM_001492.6(GDF1):āc.1091T>Cā(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 (ā ā ).
Frequency
Genomes: š 0.00028 ( 0 hom., cov: 33)
Exomes š: 0.00020 ( 0 hom. )
Consequence
GDF1
NM_001492.6 missense
NM_001492.6 missense
Scores
9
7
2
Clinical Significance
Conservation
PhyloP100: 7.14
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 Pathogenic. Variant got 10 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
PP3
Multiple lines of computational evidence support a deleterious effect 6: AlphaMissense, Cadd, M_CAP, MutationAssessor, PROVEAN, 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 [Likely_pathogenic]. Clinvar id 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.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GDF1 | NM_001492.6 | c.1091T>C | p.Met364Thr | missense_variant | 8/8 | ENST00000247005.8 | NP_001483.3 | |
CERS1 | NM_021267.5 | c.*1360T>C | 3_prime_UTR_variant | 8/8 | ENST00000623882.4 | NP_067090.1 | ||
GDF1 | NM_001387438.1 | c.1091T>C | p.Met364Thr | missense_variant | 5/5 | NP_001374367.1 | ||
CERS1 | NM_001387440.1 | c.*1952T>C | 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.1091T>C | p.Met364Thr | missense_variant | 8/8 | 1 | NM_001492.6 | ENSP00000247005 | P1 | |
CERS1 | ENST00000623882.4 | c.*1360T>C | 3_prime_UTR_variant | 8/8 | 1 | NM_021267.5 | ENSP00000485308 | P2 |
Frequencies
GnomAD3 genomes AF: 0.000276 AC: 42AN: 152086Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000508 AC: 93AN: 182990Hom.: 0 AF XY: 0.000526 AC XY: 52AN XY: 98798
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GnomAD4 exome AF: 0.000202 AC: 287AN: 1419596Hom.: 0 Cov.: 31 AF XY: 0.000212 AC XY: 149AN XY: 702218
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GnomAD4 genome AF: 0.000276 AC: 42AN: 152086Hom.: 0 Cov.: 33 AF XY: 0.000310 AC XY: 23AN XY: 74296
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ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:3
Likely pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 14, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31876989, 31818857, 26633542, 28991257, 31589614) - |
Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Sep 08, 2023 | In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt GDF1 protein function. ClinVar contains an entry for this variant (Variation ID: 522571). This missense change has been observed in individual(s) with congenital heart disease and/or abnormality of the cardiovascular system (PMID: 26633542, 28991257, 34958143). It is commonly reported in individuals of Ashkenazi Jewish ancestry (PMID: 28991257). This variant is present in population databases (rs374016704, gnomAD 0.9%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 364 of the GDF1 protein (p.Met364Thr). - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2020 | - - |
Heart, malformation of Pathogenic:1
Likely pathogenic, no assertion criteria provided | curation | Reproductive Health Research and Development, BGI Genomics | Jan 06, 2020 | NM_001492.4:c.1091T>C in the GDF1 gene has an allele frequency of 0.009 in Ashkenazi Jewish subpopulation in the gnomAD database. This variant has been reported to be a common cause of congenital heart disease in the Ashkenazi Jewish population and has been found in homozygosity in 10 affected individuals (PMID: 28991257). Additional evidence supports homozygosity for p.Met364Thr in CHD risk among Ashkenazim. p.Met364Thr shows remarkable violation of Hardy Weinberg equilibrium among Ashkenazi CHD cases, (P = 5.5x10-38, 1-df chi-square test with Yates correction). In contrast, among 302 Ashkenazi autism parental controls and 926 additional Ashkenazi adults from an independent cohort without CHD, there were no homozygotes and 12 heterozygotes (two-sided Fisher's Exact P = 2.8x10-9). Pathogenic computational verdict because pathogenic predictions from DANN, DEOGEN2, MutationTaster, REVEL and SIFTT. We interprete this variant as Pathogenic/Likely pathogenic. ACMG/AMP Criteria applied: PS4; PM3. - |
Congenital heart defects, multiple types, 6 Pathogenic:1
Pathogenic, no assertion criteria provided | literature only | OMIM | Apr 18, 2018 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;.
M_CAP
Pathogenic
D
MetaRNN
Benign
T;T
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;.
MutationTaster
Benign
D;D
PROVEAN
Pathogenic
D;.
REVEL
Pathogenic
Sift
Pathogenic
D;.
Sift4G
Pathogenic
D;D
Vest4
MVP
MPC
ClinPred
T
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