dbSNP rs3745647: GCDH:c.127+48T>C (chr19-12891570-T-C) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.0910

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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	Effect	Exon rank	MANE	Protein
GCDH	NM_000159.4 link	c.127+48T>C	intron_variant	Intron 3 of 11	ENST00000222214.10	NP_000150.1
GCDH	NM_013976.5 link	c.127+48T>C	intron_variant	Intron 3 of 11		NP_039663.1
GCDH	NR_102317.1 link	n.283T>C	non_coding_transcript_exon_variant	Exon 3 of 11
GCDH	NR_102316.1 link	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 link	c.127+48T>C		intron_variant	Intron 3 of 11	1	NM_000159.4	ENSP00000222214.4		Q92947-1

Frequencies

GnomAD3 genomes

AF:

0.0480

AC:

7303

AN:

152178

Hom.:

243

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.0357

AC XY:

25925

AN XY:

727104

show subpopulations

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.:

AF XY:

0.0452

AC XY:

3370

AN XY:

74480

show subpopulations

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.:

Bravo

AF:

0.0514

Asia WGS

AF:

0.0260

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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

BayesDel_noAF

Benign

-0.88

CADD

Benign

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over