19-12891169-G-GT

Variant names:

• chr19-12891169-G-GT
• rs886054239
• NM_000159.4:c.-67dupT

Variant summary

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

The NM_000159.4(GCDH):​c.-67dupT variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000054 in 555,494 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000054 (0 hom.)
• Consequence: GCDH NM_000159.4 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -2.81
• 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.-67dupT		5_prime_UTR_variant	Exon 1 of 12	ENST00000222214.10	NP_000150.1
GCDH	NR_102316.1	n.42dupT		non_coding_transcript_exon_variant	Exon 1 of 12
GCDH	NR_102317.1	n.42dupT		non_coding_transcript_exon_variant	Exon 1 of 11
GCDH	NM_013976.5	c.-67dupT		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.-67dupT		5_prime_UTR_variant	Exon 1 of 12	1	NM_000159.4	ENSP00000222214.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000540 AC: 3 AN: 555494 Hom.: 0 Cov.: 6 AF XY: 0.00000338 AC XY: 1 AN XY: 295914

African (AFR) AF: 0.00 AC: 0 AN: 15760

American (AMR) AF: 0.00 AC: 0 AN: 33208

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19134

East Asian (EAS) AF: 0.00 AC: 0 AN: 31664

South Asian (SAS) AF: 0.00 AC: 0 AN: 61804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33026

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2412

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 328332

Other (OTH) AF: 0.0000995 AC: 3 AN: 30154

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Elevated circulating glutaric acid concentration Uncertain:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		-2.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs886054239; hg19: chr19-13001983;