rs3745647

chr19-12891570-T-Cchr19-12891570-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000159.4(GCDH):c.127+48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.037 in 1,613,942 control chromosomes in the GnomAD database, including 1,326 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.048 (241 hom., cov: 33)
  • Exomes 𝑓: 0.036 (1085 hom.)
• Consequence: GCDH NM_000159.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.0910

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 19-12891570-T-C is Benign according to our data. Variant chr19-12891570-T-C is described in ClinVar as [Benign]. Clinvar id is 255394.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0859 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCDH	NM_000159.4	c.127+48T>C		intron_variant		ENST00000222214.10
GCDH	NM_013976.5	c.127+48T>C		intron_variant
GCDH	NR_102317.1	n.283T>C		non_coding_transcript_exon_variant	3/11
GCDH	NR_102316.1	n.235+48T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCDH	ENST00000222214.10	c.127+48T>C		intron_variant		1	NM_000159.4	P1

Frequencies

GnomAD3 genomes AF: 0.0480 AC: 7303 AN: 152178 Hom.: 243 Cov.: 33

Gnomad AFR AF: 0.0883

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0381

Gnomad ASJ AF: 0.0279

Gnomad EAS AF: 0.00770

Gnomad SAS AF: 0.0290

Gnomad FIN AF: 0.00903

Gnomad MID AF: 0.0316

Gnomad NFE AF: 0.0381

Gnomad OTH AF: 0.0417

GnomAD3 exomes AF: 0.0338 AC: 8497 AN: 251134 Hom.: 193 AF XY: 0.0328 AC XY: 4454 AN XY: 135772

Gnomad AFR exome AF: 0.0909

Gnomad AMR exome AF: 0.0254

Gnomad ASJ exome AF: 0.0256

Gnomad EAS exome AF: 0.00658

Gnomad SAS exome AF: 0.0333

Gnomad FIN exome AF: 0.0109

Gnomad NFE exome AF: 0.0377

Gnomad OTH exome AF: 0.0372

GnomAD4 exome AF: 0.0359 AC: 52451 AN: 1461646 Hom.: 1085 Cov.: 35 AF XY: 0.0357 AC XY: 25925 AN XY: 727104

Gnomad4 AFR exome AF: 0.0926

Gnomad4 AMR exome AF: 0.0264

Gnomad4 ASJ exome AF: 0.0258

Gnomad4 EAS exome AF: 0.0122

Gnomad4 SAS exome AF: 0.0323

Gnomad4 FIN exome AF: 0.0123

Gnomad4 NFE exome AF: 0.0369

Gnomad4 OTH exome AF: 0.0384

GnomAD4 genome AF: 0.0480 AC: 7307 AN: 152296 Hom.: 241 Cov.: 33 AF XY: 0.0452 AC XY: 3370 AN XY: 74480

Gnomad4 AFR AF: 0.0883

Gnomad4 AMR AF: 0.0380

Gnomad4 ASJ AF: 0.0279

Gnomad4 EAS AF: 0.00772

Gnomad4 SAS AF: 0.0286

Gnomad4 FIN AF: 0.00903

Gnomad4 NFE AF: 0.0381

Gnomad4 OTH AF: 0.0412

Alfa AF: 0.0421 Hom.: 38

Bravo AF: 0.0514

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Glutaric aciduria, type 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	13
Dann	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs3745647; hg19: chr19-13002384;