rs535143891

Positions:

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

The NM_000170.3(GLDC):c.52G>T(p.Gly18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 1,259,152 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0066 ( 2 hom., cov: 32)

Exomes 𝑓: 0.0095 ( 76 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:9

Conservation

PhyloP100: 0.822

Variant links:

Genes affected

GLDC (HGNC:4313): (glycine decarboxylase) Degradation of glycine is brought about by the glycine cleavage system, which is composed of four mitochondrial protein components: P protein (a pyridoxal phosphate-dependent glycine decarboxylase), H protein (a lipoic acid-containing protein), T protein (a tetrahydrofolate-requiring enzyme), and L protein (a lipoamide dehydrogenase). The protein encoded by this gene is the P protein, which binds to glycine and enables the methylamine group from glycine to be transferred to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH).[provided by RefSeq, Jan 2010]

GLDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0070572793).

BP6

Variant 9-6645448-C-A is Benign according to our data. Variant chr9-6645448-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367208.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=3}. Variant chr9-6645448-C-A is described in Lovd as [Benign]. Variant chr9-6645448-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.52G>T	p.Gly18Cys	missense_variant	1/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8 linkuse as main transcript	c.52G>T	p.Gly18Cys	missense_variant	1/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes

AF:

0.00659

AC:

1000

AN:

151778

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00174

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00551

Gnomad ASJ

AF:

0.00144

Gnomad EAS

AF:

0.000194

Gnomad SAS

AF:

0.00372

Gnomad FIN

AF:

0.0156

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00938

Gnomad OTH

AF:

0.00576

GnomAD3 exomes

AF:

0.0155

AC:

AN:

4648

Hom.:

AF XY:

0.0152

AC XY:

AN XY:

2834

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00711

Gnomad FIN exome

AF:

0.0302

Gnomad NFE exome

AF:

0.0154

Gnomad OTH exome

AF:

0.00926

GnomAD4 exome

AF:

0.00952

AC:

10545

AN:

1107266

Hom.:

Cov.:

AF XY:

0.00945

AC XY:

5027

AN XY:

531864

show subpopulations

Gnomad4 AFR exome

AF:

0.00156

Gnomad4 AMR exome

AF:

0.00320

Gnomad4 ASJ exome

AF:

0.000874

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00364

Gnomad4 FIN exome

AF:

0.0222

Gnomad4 NFE exome

AF:

0.0101

Gnomad4 OTH exome

AF:

0.00692

GnomAD4 genome

AF:

0.00658

AC:

1000

AN:

151886

Hom.:

Cov.:

AF XY:

0.00696

AC XY:

517

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.00173

Gnomad4 AMR

AF:

0.00551

Gnomad4 ASJ

AF:

0.00144

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.00373

Gnomad4 FIN

AF:

0.0156

Gnomad4 NFE

AF:

0.00938

Gnomad4 OTH

AF:

0.00570

Alfa

AF:

0.00309

Hom.:

Bravo

AF:

0.00531

ExAC

AF:

0.00274

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:9

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Non-ketotic hyperglycinemia

Uncertain:1Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -

not provided

Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 04, 2018	This variant is associated with the following publications: (PMID: 22171071) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	GLDC: PP3, BS1, BS2 -

not specified

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2021	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

GLDC-related disorder

Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 09, 2024

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Benign

-0.16

Eigen_PC

Benign

-0.18

FATHMM_MKL

Benign

0.31

LIST_S2

Benign

0.42

MetaRNN

Benign

0.0071

MetaSVM

Pathogenic

0.90

MutationAssessor

Benign

0.0

MutationTaster

Benign

0.74

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

0.010

REVEL

Uncertain

0.48

Sift

Benign

0.14

Sift4G

Benign

0.17

Polyphen

0.97

Vest4

0.38

MPC

0.31

ClinPred

0.051

GERP RS

3.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.16

gMVP

0.48

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

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