ENST00000590627.5:n.11G>A

Variant names:

• chr19-12891190-G-A
• rs952257144
• ENST00000590627.5:n.11G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The ENST00000590627.5(GCDH):​n.11G>A variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 774,618 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: GCDH ENST00000590627.5 non_coding_transcript_exon
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0140
• Publications: 0 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.-47G>A		5_prime_UTR_variant	Exon 1 of 12	ENST00000222214.10	NP_000150.1
GCDH	NR_102316.1	n.62G>A		non_coding_transcript_exon_variant	Exon 1 of 12
GCDH	NR_102317.1	n.62G>A		non_coding_transcript_exon_variant	Exon 1 of 11
GCDH	NM_013976.5	c.-47G>A		5_prime_UTR_variant	Exon 1 of 12		NP_039663.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.-47G>A		5_prime_UTR_variant	Exon 1 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000129 AC: 8 AN: 622354 Hom.: 0 Cov.: 8 AF XY: 0.0000152 AC XY: 5 AN XY: 329768

African (AFR) AF: 0.00 AC: 0 AN: 17172

American (AMR) AF: 0.0000290 AC: 1 AN: 34440

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 20246

East Asian (EAS) AF: 0.00 AC: 0 AN: 32160

South Asian (SAS) AF: 0.0000307 AC: 2 AN: 65170

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2582

European-Non Finnish (NFE) AF: 0.0000130 AC: 5 AN: 384428

Other (OTH) AF: 0.00 AC: 0 AN: 32450

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152264 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74390

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41476

American (AMR) AF: 0.0000654 AC: 1 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5200

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68048

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.000203), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glutaric aciduria, type 1 Uncertain:1

Jan 22, 2019

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: PM2. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	9.0
DANN	Benign	0.61
PhyloP100		0.014
PromoterAI		0.66	Over-expression

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.30		Position offset: 2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs952257144; hg19: chr19-13002004;