rs1555751089
Positions:
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PM2PP5_Moderate
The NM_000159.4(GCDH):c.1054C>T(p.Gln352*) variant causes a stop gained change. The variant allele was found at a frequency of 0.000000684 in 1,461,444 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 Pathogenic (★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
GCDH
NM_000159.4 stop_gained
NM_000159.4 stop_gained
Scores
5
1
1
Clinical Significance
Conservation
PhyloP100: 4.75
Genes affected
GCDH (HGNC:4189): (glutaryl-CoA dehydrogenase) The protein encoded by this gene belongs to the acyl-CoA dehydrogenase family. It catalyzes the oxidative decarboxylation of glutaryl-CoA to crotonyl-CoA and CO(2) in the degradative pathway of L-lysine, L-hydroxylysine, and L-tryptophan metabolism. It uses electron transfer flavoprotein as its electron acceptor. The enzyme exists in the mitochondrial matrix as a homotetramer of 45-kD subunits. Mutations in this gene result in the metabolic disorder glutaric aciduria type 1, which is also known as glutaric acidemia type I. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 12. [provided by RefSeq, Mar 2013]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 19-12897400-C-T is Pathogenic according to our data. Variant chr19-12897400-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 554539.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-12897400-C-T is described in Lovd as [Pathogenic]. Variant chr19-12897400-C-T is described in Lovd as [Pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.1054C>T | p.Gln352* | stop_gained | 10/12 | ENST00000222214.10 | NP_000150.1 | |
GCDH | NM_013976.5 | c.1054C>T | p.Gln352* | stop_gained | 10/12 | NP_039663.1 | ||
GCDH | NR_102316.1 | n.1217C>T | non_coding_transcript_exon_variant | 10/12 | ||||
GCDH | NR_102317.1 | n.1435C>T | non_coding_transcript_exon_variant | 9/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.1054C>T | p.Gln352* | stop_gained | 10/12 | 1 | NM_000159.4 | ENSP00000222214.4 |
Frequencies
GnomAD3 genomes Cov.: 32
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461444Hom.: 0 Cov.: 33 AF XY: 0.00000138 AC XY: 1AN XY: 727030
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1461444
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33
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1
AN XY:
727030
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GnomAD4 genome Cov.: 32
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Glutaric aciduria, type 1 Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Oct 27, 2017 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
Vest4
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
DS_DL_spliceai
Position offset: 28
Find out detailed SpliceAI scores and Pangolin per-transcript scores at