chr19-12891205-A-G

Variant names:

• chr19-12891205-A-G
• rs990871155
• ENST00000591470.5:c.-100A>G

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2 BP4_Strong BP6_Moderate

The NM_000159.4(GCDH):​c.-35+3A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000454 in 881,382 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GCDH NM_000159.4 splice_region, intron
• Scores: Splicing: ADA: 0.0003448
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.33
• 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: Genomics England PanelApp, G2P, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet, Myriad Women’s Health

ACMG classification

Our verdict: Likely_benign. The variant received -4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 19-12891205-A-G is Benign according to our data. Variant chr19-12891205-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 388409.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000159.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	NM_000159.4	MANE Select	c.-35+3A>G		splice_region intron	N/A	NP_000150.1	Q92947-1
	GCDH	NM_013976.5		c.-35+3A>G		splice_region intron	N/A	NP_039663.1	Q92947-2
	GCDH	NR_102316.1		n.74+3A>G		splice_region intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000591470.5	TSL:1	c.-100A>G		5_prime_UTR	Exon 1 of 11	ENSP00000466845.1	Q92947-1
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.-35+3A>G		splice_region intron	N/A	ENSP00000222214.4	Q92947-1
	GCDH	ENST00000590627.5	TSL:1	n.23+3A>G		splice_region intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152266 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

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: 0.00000274 AC: 2 AN: 729116 Hom.: 0 Cov.: 10 AF XY: 0.00000522 AC XY: 2 AN XY: 383090

African (AFR) AF: 0.0000513 AC: 1 AN: 19494

American (AMR) AF: 0.00 AC: 0 AN: 35354

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21108

East Asian (EAS) AF: 0.00 AC: 0 AN: 33464

South Asian (SAS) AF: 0.00 AC: 0 AN: 68380

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34436

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2748

European-Non Finnish (NFE) AF: 0.00000209 AC: 1 AN: 478026

Other (OTH) AF: 0.00 AC: 0 AN: 36106

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152266 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74388

African (AFR) AF: 0.0000241 AC: 1 AN: 41478

American (AMR) AF: 0.0000654 AC: 1 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

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

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	0.19
DANN	Benign	0.69
PhyloP100		-2.3
PromoterAI		-0.21	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.3

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00034
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.10		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: rs990871155; hg19: chr19-13002019;