rs754119942
Positions:
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_000170.3(GLDC):āc.1517G>Cā(p.Arg506Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000745 in 1,610,300 control chromosomes in the GnomAD database, with no homozygous occurrence. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 32)
Exomes š: 0.0000069 ( 0 hom. )
Consequence
GLDC
NM_000170.3 missense
NM_000170.3 missense
Scores
7
12
Clinical Significance
Conservation
PhyloP100: 2.63
Genes affected
GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GLDC | NM_000170.3 | c.1517G>C | p.Arg506Thr | missense_variant | 12/25 | ENST00000321612.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GLDC | ENST00000321612.8 | c.1517G>C | p.Arg506Thr | missense_variant | 12/25 | 1 | NM_000170.3 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000199 AC: 5AN: 251476Hom.: 0 AF XY: 0.0000294 AC XY: 4AN XY: 135912
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GnomAD4 exome AF: 0.00000686 AC: 10AN: 1458138Hom.: 0 Cov.: 28 AF XY: 0.00000965 AC XY: 7AN XY: 725684
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GnomAD4 genome ? AF: 0.0000131 AC: 2AN: 152162Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1AN XY: 74322
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Non-ketotic hyperglycinemia Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 31, 2022 | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 506 of the GLDC protein (p.Arg506Thr). This variant is present in population databases (rs754119942, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with GLDC-related conditions. ClinVar contains an entry for this variant (Variation ID: 531770). 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 not expected to disrupt GLDC protein function. 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. - |
Uncertain significance, no assertion criteria provided | clinical testing | Natera, Inc. | Oct 28, 2019 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Uncertain
CADD
Benign
DANN
Benign
DEOGEN2
Benign
T
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Benign
N
MutationTaster
Benign
D
PrimateAI
Benign
T
PROVEAN
Benign
N
REVEL
Uncertain
Sift
Benign
T
Sift4G
Benign
T
Polyphen
B
Vest4
MutPred
Gain of phosphorylation at R506 (P = 0.0472);
MVP
MPC
ClinPred
T
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