19-12897793-G-T

Variant names:

• chr19-12897793-G-T
• rs1060218
• NM_000159.4:c.1173G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000159.4(GCDH):​c.1173G>T​(p.Gly391Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.351 in 1,612,912 control chromosomes in the GnomAD database, including 103,534 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.31 (7709 hom., cov: 30)
  • Exomes 𝑓: 0.36 (95825 hom.)
• Consequence: GCDH NM_000159.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -1.11
• Publications: 27 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: Myriad Women’s Health, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 19-12897793-G-T is Benign according to our data. Variant chr19-12897793-G-T is described in ClinVar as Benign. ClinVar VariationId is 92529.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.11 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.383 is higher than 0.05.

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.1173G>T	p.Gly391Gly	synonymous	Exon 11 of 12	NP_000150.1	Q92947-1
	GCDH	NM_013976.5		c.1173G>T	p.Gly391Gly	synonymous	Exon 11 of 12	NP_039663.1	Q92947-2
	GCDH	NR_102316.1		n.1336G>T		non_coding_transcript_exon	Exon 11 of 12

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCDH	ENST00000222214.10	TSL:1 MANE Select	c.1173G>T	p.Gly391Gly	synonymous	Exon 11 of 12	ENSP00000222214.4	Q92947-1
	GCDH	ENST00000591470.5	TSL:1	c.1173G>T	p.Gly391Gly	synonymous	Exon 10 of 11	ENSP00000466845.1	Q92947-1
	GCDH	ENST00000714069.1		c.1173G>T	p.Gly391Gly	synonymous	Exon 11 of 13	ENSP00000519360.1	A0AAQ5BHD5

Frequencies

GnomAD3 genomes AF: 0.307 AC: 46581 AN: 151716 Hom.: 7691 Cov.: 30

Gnomad AFR AF: 0.202

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.390

Gnomad ASJ AF: 0.284

Gnomad EAS AF: 0.146

Gnomad SAS AF: 0.264

Gnomad FIN AF: 0.296

Gnomad MID AF: 0.301

Gnomad NFE AF: 0.369

Gnomad OTH AF: 0.317

GnomAD2 exomes AF: 0.330 AC: 83034 AN: 251404 AF XY: 0.328

Gnomad AFR exome AF: 0.199

Gnomad AMR exome AF: 0.447

Gnomad ASJ exome AF: 0.286

Gnomad EAS exome AF: 0.139

Gnomad FIN exome AF: 0.301

Gnomad NFE exome AF: 0.370

Gnomad OTH exome AF: 0.338

GnomAD4 exome AF: 0.355 AC: 519119 AN: 1461078 Hom.: 95825 Cov.: 35 AF XY: 0.352 AC XY: 255790 AN XY: 726844

African (AFR) AF: 0.189 AC: 6330 AN: 33462

American (AMR) AF: 0.441 AC: 19740 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 7399 AN: 26134

East Asian (EAS) AF: 0.130 AC: 5173 AN: 39696

South Asian (SAS) AF: 0.272 AC: 23422 AN: 86248

European-Finnish (FIN) AF: 0.307 AC: 16372 AN: 53388

Middle Eastern (MID) AF: 0.298 AC: 1719 AN: 5766

European-Non Finnish (NFE) AF: 0.377 AC: 418806 AN: 1111292

Other (OTH) AF: 0.334 AC: 20158 AN: 60374

GnomAD4 genome AF: 0.307 AC: 46632 AN: 151834 Hom.: 7709 Cov.: 30 AF XY: 0.303 AC XY: 22507 AN XY: 74198

African (AFR) AF: 0.202 AC: 8352 AN: 41424

American (AMR) AF: 0.391 AC: 5959 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.284 AC: 986 AN: 3468

East Asian (EAS) AF: 0.145 AC: 750 AN: 5156

South Asian (SAS) AF: 0.264 AC: 1269 AN: 4800

European-Finnish (FIN) AF: 0.296 AC: 3130 AN: 10576

Middle Eastern (MID) AF: 0.299 AC: 88 AN: 294

European-Non Finnish (NFE) AF: 0.369 AC: 25077 AN: 67884

Other (OTH) AF: 0.322 AC: 677 AN: 2100

Alfa AF: 0.350 Hom.: 14819

Bravo AF: 0.313

Asia WGS AF: 0.250 AC: 870 AN: 3478

EpiCase AF: 0.369

EpiControl AF: 0.368

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glutaric aciduria, type 1 (4)
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Elevated circulating glutaric acid concentration (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	0.77
DANN	Benign	0.89
PhyloP100		-1.1
PromoterAI		-0.045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs1060218; hg19: chr19-13008607; COSMIC: COSV53365541; COSMIC: COSV53365541;