19-12891219-A-G

Variant summary

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

The ENST00000591470.5(GCDH):c.-86A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.953 in 1,048,340 control chromosomes in the GnomAD database, including 476,181 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.96 (70722 hom., cov: 34)
  • Exomes 𝑓: 0.95 (405459 hom.)
• Consequence: GCDH ENST00000591470.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.318

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=-0.79).
• BP6: Variant 19-12891219-A-G is Benign according to our data. Variant chr19-12891219-A-G is described in ClinVar as [Benign]. Clinvar id is 1172947.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.983 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.-35+17A>G		intron_variant		ENST00000222214.10
GCDH	NM_013976.5	c.-35+17A>G		intron_variant
GCDH	NR_102316.1	n.74+17A>G		intron_variant, non_coding_transcript_variant
GCDH	NR_102317.1	n.74+17A>G		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.-35+17A>G		intron_variant		1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.963 AC: 146623 AN: 152242 Hom.: 70665 Cov.: 34

Gnomad AFR AF: 0.991

Gnomad AMI AF: 0.970

Gnomad AMR AF: 0.957

Gnomad ASJ AF: 0.885

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.972

Gnomad FIN AF: 0.988

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.945

Gnomad OTH AF: 0.941

GnomAD4 exome AF: 0.951 AC: 852026 AN: 895980 Hom.: 405459 Cov.: 12 AF XY: 0.951 AC XY: 439824 AN XY: 462694

Gnomad4 AFR exome AF: 0.989

Gnomad4 AMR exome AF: 0.961

Gnomad4 ASJ exome AF: 0.887

Gnomad4 EAS exome AF: 1.00

Gnomad4 SAS exome AF: 0.964

Gnomad4 FIN exome AF: 0.987

Gnomad4 NFE exome AF: 0.946

Gnomad4 OTH exome AF: 0.947

GnomAD4 genome AF: 0.963 AC: 146738 AN: 152360 Hom.: 70722 Cov.: 34 AF XY: 0.965 AC XY: 71898 AN XY: 74488

Gnomad4 AFR AF: 0.991

Gnomad4 AMR AF: 0.957

Gnomad4 ASJ AF: 0.885

Gnomad4 EAS AF: 1.00

Gnomad4 SAS AF: 0.972

Gnomad4 FIN AF: 0.988

Gnomad4 NFE AF: 0.945

Gnomad4 OTH AF: 0.942

Alfa AF: 0.966 Hom.: 3669

Bravo AF: 0.960

Asia WGS AF: 0.982 AC: 3414 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Glutaric aciduria, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
Cadd	Benign	5.8
Dann	Benign	0.48

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: rs7251834; hg19: chr19-13002033;