rs114759170

Variant names:

• chr19-12897705-C-A
• rs114759170
• NM_000159.4:c.1085C>A

Your query was ambiguous. Multiple possible variants found:

• chr19-12897705-C-A
• chr19-12897705-C-T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 2P and 16B. PM1 BP4_Strong BP6_Very_Strong BS2

The NM_000159.4(GCDH):​c.1085C>A​(p.Ala362Asp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000888 in 1,614,112 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A362V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0042 (4 hom., cov: 31)
  • Exomes 𝑓: 0.00054 (3 hom.)
• Consequence: GCDH NM_000159.4 missense, splice_region
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.28
• 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: Myriad Women’s Health, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 7 uncertain in NM_000159.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.009075999).
• BP6: Variant 19-12897705-C-A is Benign according to our data. Variant chr19-12897705-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 459946.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

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.1085C>A	p.Ala362Asp	missense splice_region	Exon 11 of 12	NP_000150.1	Q92947-1
	GCDH	NM_013976.5		c.1085C>A	p.Ala362Asp	missense splice_region	Exon 11 of 12	NP_039663.1	Q92947-2
	GCDH	NR_102316.1		n.1248C>A		splice_region 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.1085C>A	p.Ala362Asp	missense splice_region	Exon 11 of 12	ENSP00000222214.4	Q92947-1
	GCDH	ENST00000591470.5	TSL:1	c.1085C>A	p.Ala362Asp	missense splice_region	Exon 10 of 11	ENSP00000466845.1	Q92947-1
	GCDH	ENST00000714069.1		c.1085C>A	p.Ala362Asp	missense splice_region	Exon 11 of 13	ENSP00000519360.1	A0AAQ5BHD5

Frequencies

GnomAD3 genomes AF: 0.00423 AC: 643 AN: 152134 Hom.: 4 Cov.: 31

Gnomad AFR AF: 0.0144

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.000265

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00119 AC: 298 AN: 251392 AF XY: 0.00104

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000237

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000539 AC: 788 AN: 1461860 Hom.: 3 Cov.: 32 AF XY: 0.000479 AC XY: 348 AN XY: 727236

African (AFR) AF: 0.0149 AC: 499 AN: 33476

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53408

Middle Eastern (MID) AF: 0.00173 AC: 10 AN: 5768

European-Non Finnish (NFE) AF: 0.000125 AC: 139 AN: 1111994

Other (OTH) AF: 0.00106 AC: 64 AN: 60396

GnomAD4 genome AF: 0.00424 AC: 645 AN: 152252 Hom.: 4 Cov.: 31 AF XY: 0.00419 AC XY: 312 AN XY: 74436

African (AFR) AF: 0.0144 AC: 600 AN: 41534

American (AMR) AF: 0.00131 AC: 20 AN: 15294

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68012

Other (OTH) AF: 0.00331 AC: 7 AN: 2114

Alfa AF: 0.00160 Hom.: 3

Bravo AF: 0.00487

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00139 AC: 169

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000356

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glutaric aciduria, type 1 (3)
-	-	3	not provided (3)
-	-	1	GCDH-related disorder (1)
-	-	1	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.10
CADD	Benign	14
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.26
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0091	T
MetaSVM	Uncertain	0.036	D
MutationAssessor	Benign	1.7	L
PhyloP100		2.3
PrimateAI	Uncertain	0.51	T
PROVEAN	Uncertain	-2.5	N
REVEL	Uncertain	0.34
Sift	Benign	0.090	T
Sift4G	Benign	0.20	T
Polyphen		0.0010	B
Vest4		0.37
MVP		0.92
MPC		0.58
ClinPred		0.0083	T
GERP RS		2.2
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.55
gMVP		0.97
Mutation Taster		=50/50

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: rs114759170; hg19: chr19-13008519;