Variant rs763739291 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_000159.4(GCDH):c.557G>A(p.Ser186Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S186C) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000027 ( 0 hom. )

Consequence

GCDH
NM_000159.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 9.48

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]

GCDH links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1

In a binding_site (size 9) in uniprot entity GCDH_HUMAN there are 23 pathogenic changes around while only 0 benign (100%) in NM_000159.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-12896042-A-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.989

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
GCDH	NM_000159.4 link	c.557G>A	p.Ser186Asn	missense_variant	7/12	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.557G>A	p.Ser186Asn	missense_variant	7/12		NP_039663.1
GCDH	NR_102316.1 link	n.720G>A		non_coding_transcript_exon_variant	7/12
GCDH	NR_102317.1 link	n.973G>A		non_coding_transcript_exon_variant	6/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10 link	c.557G>A	p.Ser186Asn	missense_variant	7/12	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000119

AC:

AN:

251450

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000270

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000247

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.000119

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.92

BayesDel_addAF

Pathogenic

0.25

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.96

D;D

Eigen

Pathogenic

1.1

Eigen_PC

Pathogenic

0.97

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

.;D

M_CAP

Pathogenic

0.82

MetaRNN

Pathogenic

0.99

D;D

MetaSVM

Pathogenic

0.92

MutationAssessor

Pathogenic

3.3

M;M

PrimateAI

Uncertain

0.52

PROVEAN

Uncertain

-3.0

D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;D

Vest4

0.91

MutPred

0.87

Loss of glycosylation at S186 (P = 0.0189);Loss of glycosylation at S186 (P = 0.0189);

MVP

1.0

MPC

1.1

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.94

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over