rs75430014
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Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 0P and 7B. BP4_ModerateBP6BS2
The NM_000159.4(GCDH):c.271+3G>A variant causes a splice donor region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000279 in 1,614,224 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: 𝑓 0.0017 ( 5 hom., cov: 32)
Exomes 𝑓: 0.00013 ( 0 hom. )
Consequence
GCDH
NM_000159.4 splice_donor_region, intron
NM_000159.4 splice_donor_region, intron
Scores
2
Splicing: ADA: 0.001554
2
Clinical Significance
Conservation
PhyloP100: 3.28
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 Benign. Variant got -7 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.38).
BP6
?
Variant 19-12891977-G-A is Benign according to our data. Variant chr19-12891977-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 235597.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=2}. Variant chr19-12891977-G-A is described in Lovd as [Likely_benign]. Variant chr19-12891977-G-A is described in Lovd as [Benign].
BS2
?
High Homozygotes in GnomAd4 at 5 AR gene
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
GCDH | NM_000159.4 | c.271+3G>A | splice_donor_region_variant, intron_variant | ENST00000222214.10 | |||
GCDH | NM_013976.5 | c.271+3G>A | splice_donor_region_variant, intron_variant | ||||
GCDH | NR_102316.1 | n.379+3G>A | splice_donor_region_variant, intron_variant, non_coding_transcript_variant | ||||
GCDH | NR_102317.1 | n.687+3G>A | splice_donor_region_variant, intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
GCDH | ENST00000222214.10 | c.271+3G>A | splice_donor_region_variant, intron_variant | 1 | NM_000159.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00157 AC: 239AN: 152214Hom.: 1 Cov.: 32
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GnomAD3 exomes AF: 0.000358 AC: 90AN: 251398Hom.: 0 AF XY: 0.000250 AC XY: 34AN XY: 135890
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GnomAD4 exome AF: 0.000133 AC: 194AN: 1461892Hom.: 0 Cov.: 33 AF XY: 0.0000976 AC XY: 71AN XY: 727248
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GnomAD4 genome ? AF: 0.00169 AC: 257AN: 152332Hom.: 5 Cov.: 32 AF XY: 0.00183 AC XY: 136AN XY: 74492
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:5
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Uncertain:1Benign:2
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics | Jun 04, 2015 | - - |
Likely benign, no assertion criteria provided | clinical testing | Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2019 | - - |
Glutaric aciduria, type 1 Benign:2
Likely benign, no assertion criteria provided | clinical testing | Natera, Inc. | May 29, 2020 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | - - |
not specified Benign:1
Benign, no assertion criteria provided | clinical testing | Clinical Genetics, Academic Medical Center | - | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Splicing
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dbscSNV1_ADA
Benign
dbscSNV1_RF
Benign
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at