19-12891219-A-T

Variant names:

• chr19-12891219-A-T
• rs7251834
• ENST00000591470.5:c.-86A>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The ENST00000591470.5(GCDH):​c.-86A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCDH ENST00000591470.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.318
• Publications: 4 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.-35+17A>T		intron_variant	Intron 1 of 11	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.-35+17A>T		intron_variant	Intron 1 of 11		NP_039663.1
GCDH	NR_102316.1	n.74+17A>T		intron_variant	Intron 1 of 11
GCDH	NR_102317.1	n.74+17A>T		intron_variant	Intron 1 of 10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.-35+17A>T		intron_variant	Intron 1 of 11	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 896306 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 462850

African (AFR) AF: 0.00 AC: 0 AN: 22902

American (AMR) AF: 0.00 AC: 0 AN: 36560

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22254

East Asian (EAS) AF: 0.00 AC: 0 AN: 34870

South Asian (SAS) AF: 0.00 AC: 0 AN: 72502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 35206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3074

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 627212

Other (OTH) AF: 0.00 AC: 0 AN: 41726

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.2
DANN	Benign	0.49
PhyloP100		0.32
PromoterAI		-0.076	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3

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: rs7251834; hg19: chr19-13002033;