rs1060218

Positions:

• chr19-12897793-G-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000159.4(GCDH):​c.1173G>T​(p.Gly391=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,612,912 control chromosomes in the GnomAD database, including 103,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7709 hom., cov: 30)
  • Exomes 𝑓: 0.36 (95825 hom.)
• Consequence: GCDH NM_000159.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -1.11

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]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-12897793-G-T is Benign according to our data. Variant chr19-12897793-G-T is described in ClinVar as [Benign]. Clinvar id is 92529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-12897793-G-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.1173G>T	p.Gly391=	synonymous_variant	11/12	ENST00000222214.10
GCDH	NM_013976.5	c.1173G>T	p.Gly391=	synonymous_variant	11/12
GCDH	NR_102316.1	n.1336G>T		non_coding_transcript_exon_variant	11/12
GCDH	NR_102317.1	n.1554G>T		non_coding_transcript_exon_variant	10/11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.1173G>T	p.Gly391=	synonymous_variant	11/12	1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46581 AN: 151716 Hom.: 7691 Cov.: 30

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.317

GnomAD3 exomes AF: 0.330 AC: 83034 AN: 251404 Hom.: 14792 AF XY: 0.328 AC XY: 44535 AN XY: 135900

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.139

Gnomad SAS exome AF: 0.267

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.355 AC: 519119 AN: 1461078 Hom.: 95825 Cov.: 35 AF XY: 0.352 AC XY: 255790 AN XY: 726844

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.441

Gnomad4 ASJ exome AF: 0.283

Gnomad4 EAS exome AF: 0.130

Gnomad4 SAS exome AF: 0.272

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.377

Gnomad4 OTH exome AF: 0.334

GnomAD4 genome AF: 0.307 AC: 46632 AN: 151834 Hom.: 7709 Cov.: 30 AF XY: 0.303 AC XY: 22507 AN XY: 74198

Gnomad4 AFR AF: 0.202

Gnomad4 AMR AF: 0.391

Gnomad4 ASJ AF: 0.284

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.264

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.369

Gnomad4 OTH AF: 0.322

Alfa AF: 0.352 Hom.: 12125

Bravo AF: 0.313

Asia WGS AF: 0.250 AC: 870 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.368

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Benign:4

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 13, 2018	- -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Feb 16, 2016	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -

Elevated circulating glutaric acid concentration Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.77
DANN	Benign	0.89
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Other links and lift over

dbSNP: rs1060218; hg19: chr19-13008607; COSMIC: COSV53365541; COSMIC: COSV53365541;