rs12004164

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_000170.3(GLDC):c.666T>C(p.Asp222Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,608,470 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 141 hom., cov: 32)

Exomes 𝑓: 0.0036 ( 133 hom. )

Consequence

GLDC
NM_000170.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.874

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

glycine encephalopathy
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
glycine encephalopathy 1
Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
infantile glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
neonatal glycine encephalopathy
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
atypical glycine encephalopathy
Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

GLDC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.57).

BP6

Variant 9-6606639-A-G is Benign according to our data. Variant chr9-6606639-A-G is described in ClinVar as [Benign]. Clinvar id is 367201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.874 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.666T>C	p.Asp222Asp	synonymous_variant	Exon 5 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.666T>C	p.Asp222Asp	synonymous_variant	Exon 5 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.0242

AC:

3688

AN:

152166

Hom.:

137

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0796

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0129

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00269

Gnomad SAS

AF:

0.0215

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.000573

Gnomad OTH

AF:

0.0158

GnomAD2 exomes

AF:

0.00946

AC:

2380

AN:

251462

AF XY:

0.00900

show subpopulations

Gnomad AFR exome

AF:

0.0815

Gnomad AMR exome

AF:

0.00480

Gnomad ASJ exome

AF:

0.0000992

Gnomad EAS exome

AF:

0.00245

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000668

Gnomad OTH exome

AF:

0.00619

GnomAD4 exome

AF:

0.00360

AC:

5238

AN:

1456186

Hom.:

133

Cov.:

AF XY:

0.00384

AC XY:

2780

AN XY:

724890

show subpopulations

African (AFR)

AF:

0.0730

AC:

2393

AN:

32794

American (AMR)

AF:

0.00552

AC:

247

AN:

44714

Ashkenazi Jewish (ASJ)

AF:

0.0000383

AC:

AN:

26100

East Asian (EAS)

AF:

0.000933

AC:

AN:

39674

South Asian (SAS)

AF:

0.0191

AC:

1645

AN:

86072

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00469

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000383

AC:

424

AN:

1107476

Other (OTH)

AF:

0.00771

AC:

464

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.421

Heterozygous variant carriers

262

523

785

1046

1308

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0244

AC:

3715

AN:

152284

Hom.:

141

Cov.:

AF XY:

0.0244

AC XY:

1818

AN XY:

74478

show subpopulations

African (AFR)

AF:

0.0799

AC:

3319

AN:

41550

American (AMR)

AF:

0.0129

AC:

197

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00270

AC:

AN:

5190

South Asian (SAS)

AF:

0.0209

AC:

101

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00680

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000573

AC:

AN:

68018

Other (OTH)

AF:

0.0203

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

174

348

523

697

871

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0113

Hom.:

Bravo

AF:

0.0273

Asia WGS

AF:

0.0440

AC:

154

AN:

3478

EpiCase

AF:

0.000872

EpiControl

AF:

0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Aug 10, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

Jun 29, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

GLDC-related disorder

Benign:1

Feb 28, 2019

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

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

BayesDel_noAF

Benign

-0.57

CADD

Benign

3.2

(source)

DANN

Benign

0.51

PhyloP100

0.87

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

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rs12004164

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over