rs1555750471

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000159.4(GCDH):ā€‹c.550A>Gā€‹(p.Ser184Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 0.0000021 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

9
10

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.56
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a strand (size 2) in uniprot entity GCDH_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_000159.4
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GCDHNM_000159.4 linkuse as main transcriptc.550A>G p.Ser184Gly missense_variant 7/12 ENST00000222214.10 NP_000150.1
GCDHNM_013976.5 linkuse as main transcriptc.550A>G p.Ser184Gly missense_variant 7/12 NP_039663.1
GCDHNR_102316.1 linkuse as main transcriptn.713A>G non_coding_transcript_exon_variant 7/12
GCDHNR_102317.1 linkuse as main transcriptn.966A>G non_coding_transcript_exon_variant 6/11

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GCDHENST00000222214.10 linkuse as main transcriptc.550A>G p.Ser184Gly missense_variant 7/121 NM_000159.4 ENSP00000222214.4 Q92947-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
0.00000205
AC:
3
AN:
1461818
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
727212
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000504
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glutaric aciduria, type 1 Uncertain:1
Uncertain significance, criteria provided, single submitterresearchTIDEX, University of British Columbia-- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.081
BayesDel_addAF
Uncertain
0.097
D
BayesDel_noAF
Benign
-0.10
CADD
Benign
21
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.79
D;D
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.32
FATHMM_MKL
Uncertain
0.90
D
LIST_S2
Uncertain
0.96
.;D
M_CAP
Uncertain
0.12
D
MetaRNN
Uncertain
0.55
D;D
MetaSVM
Uncertain
-0.19
T
MutationAssessor
Benign
0.10
N;N
PrimateAI
Benign
0.38
T
PROVEAN
Benign
-1.3
N;.
REVEL
Uncertain
0.35
Sift
Benign
0.037
D;.
Sift4G
Benign
0.15
T;T
Polyphen
0.027
B;B
Vest4
0.45
MutPred
0.45
Loss of glycosylation at S184 (P = 0.0121);Loss of glycosylation at S184 (P = 0.0121);
MVP
0.90
MPC
0.39
ClinPred
0.54
D
GERP RS
3.0
Varity_R
0.35
gMVP
0.68

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1555750471; hg19: chr19-13006850; COSMIC: COSV53366606; COSMIC: COSV53366606; API