rs11085825

Positions:

• chr19-12896644-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000159.4(GCDH):​c.852+223C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.308 in 152,158 control chromosomes in the GnomAD database, including 7,729 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency: Genomes: 𝑓 0.31 (7729 hom., cov: 32)
• Consequence: GCDH NM_000159.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts P:1 B:7
• Conservation: PhyloP100: -0.555

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 19-12896644-C-T is Benign according to our data. Variant chr19-12896644-C-T is described in ClinVar as [Benign]. Clinvar id is 221908.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.37 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCDH	NM_000159.4	c.852+223C>T		intron_variant		ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.852+223C>T		intron_variant			NP_039663.1
GCDH	NR_102316.1	n.1015+223C>T		intron_variant
GCDH	NR_102317.1	n.1233+223C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.852+223C>T		intron_variant		1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes AF: 0.308 AC: 46774 AN: 152040 Hom.: 7712 Cov.: 32

Gnomad AFR AF: 0.212

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.377

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.266

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.304

Gnomad NFE AF: 0.367

Gnomad OTH AF: 0.324

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.308 AC: 46826 AN: 152158 Hom.: 7729 Cov.: 32 AF XY: 0.304 AC XY: 22611 AN XY: 74396

Gnomad4 AFR AF: 0.212

Gnomad4 AMR AF: 0.379

Gnomad4 ASJ AF: 0.294

Gnomad4 EAS AF: 0.145

Gnomad4 SAS AF: 0.266

Gnomad4 FIN AF: 0.296

Gnomad4 NFE AF: 0.367

Gnomad4 OTH AF: 0.329

Alfa AF: 0.356 Hom.: 12915

Bravo AF: 0.314

Asia WGS AF: 0.250 AC: 871 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1 Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glutaric aciduria, type 1 Pathogenic:1 Benign:3

Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Likely pathogenic, no assertion criteria provided	research	National Institute of Mental Health and Neurosciences	Dec 08, 2015	- -
Benign, no assertion criteria provided	curation	Reproductive Health Research and Development, BGI Genomics	Jan 06, 2020	NG_009292.1(NM_000159.3):c.852+223C>T in the gene GCDH has an allele frequency of 0.361 in Latino subpopulation in the gnomAD database. A total of 1525 homozygous occurrences are observed in the gnomAD database. Benign computational verdict because 1 benign prediction from DANN. This evidence suggests the variant to be classified as benign. ACMG/AMP criteria applied: BA1, BS2, BP4. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	May 31, 2020	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Aug 22, 2018	The c.852+223C>T variant in GCDH is classified as benign because it has been identified in 30% (9205/30886) of total chromosomes by the Genome Aggregation Database (gnomAD; http://gnomad.broadinstitute.org), including 1473 homozygotes. ACMG/AMP Criteria applied: BA1. -
Benign, criteria provided, single submitter	research	H3Africa Consortium	Oct 28, 2020	While the frequency of the alternate allele in gnoMAD v2.0.2 is 0.18, its frequency in African populations is >5%. This suggests that previous classifications of this variant as pathogenic are in error. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 14, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.50

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: rs11085825; hg19: chr19-13007458; COSMIC: COSV53366351; COSMIC: COSV53366351;