19-12891219-A-G

Variant names:

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

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.-35+17A>G variant causes a intron 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 NM_000159.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• 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: Benign. The variant received -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 rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.-35+17A>G		intron_variant	Intron 1 of 11	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5	c.-35+17A>G		intron_variant	Intron 1 of 11		NP_039663.1
GCDH	NR_102316.1	n.74+17A>G		intron_variant	Intron 1 of 11
GCDH	NR_102317.1	n.74+17A>G		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>G		intron_variant	Intron 1 of 11	1	NM_000159.4	ENSP00000222214.4

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

African (AFR) AF: 0.989 AC: 22651 AN: 22902

American (AMR) AF: 0.961 AC: 35120 AN: 36556

Ashkenazi Jewish (ASJ) AF: 0.887 AC: 19747 AN: 22252

East Asian (EAS) AF: 1.00 AC: 34868 AN: 34870

South Asian (SAS) AF: 0.964 AC: 69879 AN: 72492

European-Finnish (FIN) AF: 0.987 AC: 34761 AN: 35206

Middle Eastern (MID) AF: 0.872 AC: 2682 AN: 3074

European-Non Finnish (NFE) AF: 0.946 AC: 592821 AN: 626904

Other (OTH) AF: 0.947 AC: 39497 AN: 41724

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

African (AFR) AF: 0.991 AC: 41218 AN: 41596

American (AMR) AF: 0.957 AC: 14657 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.885 AC: 3072 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5170 AN: 5172

South Asian (SAS) AF: 0.972 AC: 4693 AN: 4830

European-Finnish (FIN) AF: 0.988 AC: 10491 AN: 10620

Middle Eastern (MID) AF: 0.830 AC: 244 AN: 294

European-Non Finnish (NFE) AF: 0.945 AC: 64315 AN: 68040

Other (OTH) AF: 0.942 AC: 1993 AN: 2116

Alfa AF: 0.957 Hom.: 15049

Bravo AF: 0.960

Asia WGS AF: 0.982 AC: 3414 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Mar 03, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glutaric aciduria, type 1 Benign:1

Jun 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	5.8
DANN	Benign	0.48
PhyloP100		0.32
PromoterAI		0.099	Neutral
Mutation Taster		=300/0	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: rs7251834; hg19: chr19-13002033;