ENST00000590627.5:n.232T>C

Variant names:

• chr19-12891570-T-C
• rs3745647
• ENST00000590627.5:n.232T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The ENST00000590627.5(GCDH):​n.232T>C variant causes a non coding transcript exon 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 ENST00000590627.5 non_coding_transcript_exon
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.0910
• Publications: 5 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=-0.88).
• BP6: Variant 19-12891570-T-C is Benign according to our data. Variant chr19-12891570-T-C is described in ClinVar as Benign. ClinVar VariationId 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 rank	MANE	Protein	UniProt
GCDH	NM_000159.4	c.127+48T>C		intron_variant	Intron 3 of 11	ENST00000222214.10	NP_000150.1
GCDH	NR_102317.1	n.283T>C		non_coding_transcript_exon_variant	Exon 3 of 11
GCDH	NM_013976.5	c.127+48T>C		intron_variant	Intron 3 of 11		NP_039663.1
GCDH	NR_102316.1	n.235+48T>C		intron_variant	Intron 3 of 11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCDH	ENST00000222214.10	c.127+48T>C		intron_variant	Intron 3 of 11	1	NM_000159.4	ENSP00000222214.4

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

GnomAD2 exomes AF: 0.0338 AC: 8497 AN: 251134 AF XY: 0.0328

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 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

African (AFR) AF: 0.0926 AC: 3100 AN: 33474

American (AMR) AF: 0.0264 AC: 1179 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0258 AC: 674 AN: 26134

East Asian (EAS) AF: 0.0122 AC: 483 AN: 39698

South Asian (SAS) AF: 0.0323 AC: 2785 AN: 86242

European-Finnish (FIN) AF: 0.0123 AC: 655 AN: 53392

Middle Eastern (MID) AF: 0.0425 AC: 239 AN: 5618

European-Non Finnish (NFE) AF: 0.0369 AC: 41017 AN: 1111980

Other (OTH) AF: 0.0384 AC: 2319 AN: 60386

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

African (AFR) AF: 0.0883 AC: 3668 AN: 41562

American (AMR) AF: 0.0380 AC: 582 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0279 AC: 97 AN: 3472

East Asian (EAS) AF: 0.00772 AC: 40 AN: 5180

South Asian (SAS) AF: 0.0286 AC: 138 AN: 4830

European-Finnish (FIN) AF: 0.00903 AC: 96 AN: 10630

Middle Eastern (MID) AF: 0.0306 AC: 9 AN: 294

European-Non Finnish (NFE) AF: 0.0381 AC: 2589 AN: 68002

Other (OTH) AF: 0.0412 AC: 87 AN: 2110

Alfa AF: 0.0432 Hom.: 39

Bravo AF: 0.0514

Asia WGS AF: 0.0260 AC: 89 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

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

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

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
AlphaMissense	Benign	0.21
BayesDel_noAF	Benign	-0.88
CADD	Benign	13
DANN	Benign	0.66
PhyloP100		-0.091
PromoterAI		0.045	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs3745647; hg19: chr19-13002384;