NM_000159.4:c.852+223C>T

Variant names:

• chr19-12896644-C-T
• rs11085825
• NM_000159.4:c.852+223C>T

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 25 publications found

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 Gene-Disease associations (from GenCC):

• glutaryl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	NM_000159.4	MANE Select	c.852+223C>T		intron	N/A	NP_000150.1
	GCDH	NM_013976.5		c.852+223C>T		intron	N/A	NP_039663.1
	GCDH	NR_102316.1		n.1015+223C>T		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.852+223C>T		intron	N/A	ENSP00000222214.4
	GCDH	ENST00000591470.5	TSL:1	c.852+223C>T		intron	N/A	ENSP00000466845.1
	GCDH	ENST00000714069.1		c.852+223C>T		intron	N/A	ENSP00000519360.1

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

African (AFR) AF: 0.212 AC: 8788 AN: 41542

American (AMR) AF: 0.379 AC: 5787 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1021 AN: 3470

East Asian (EAS) AF: 0.145 AC: 750 AN: 5156

South Asian (SAS) AF: 0.266 AC: 1283 AN: 4828

European-Finnish (FIN) AF: 0.296 AC: 3131 AN: 10588

Middle Eastern (MID) AF: 0.303 AC: 89 AN: 294

European-Non Finnish (NFE) AF: 0.367 AC: 24936 AN: 67972

Other (OTH) AF: 0.329 AC: 695 AN: 2114

Alfa AF: 0.353 Hom.: 16156

Bravo AF: 0.314

Asia WGS AF: 0.250 AC: 871 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	3	Glutaric aciduria, type 1 (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.2
DANN	Benign	0.50
PhyloP100		-0.56
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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