rs73400312

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000170.3(GLDC):c.1384C>G(p.Leu462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,522 control chromosomes in the GnomAD database, including 900 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L462L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.045 ( 420 hom., cov: 32)

Exomes 𝑓: 0.0096 ( 480 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 0.477

Publications

8 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 10 uncertain in NM_000170.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0021384656).

BP6

Variant 9-6592868-G-C is Benign according to our data. Variant chr9-6592868-G-C is described in ClinVar as [Benign]. Clinvar id is 367193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.1384C>G	p.Leu462Val	missense_variant	Exon 10 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.1384C>G	p.Leu462Val	missense_variant	Exon 10 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.0445

AC:

6773

AN:

152184

Hom.:

418

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0312

Gnomad ASJ

AF:

0.0311

Gnomad EAS

AF:

0.00423

Gnomad SAS

AF:

0.0375

Gnomad FIN

AF:

0.000377

Gnomad MID

AF:

0.0348

Gnomad NFE

AF:

0.00388

Gnomad OTH

AF:

0.0368

GnomAD2 exomes

AF:

0.0187

AC:

4701

AN:

251430

AF XY:

0.0174

show subpopulations

Gnomad AFR exome

AF:

0.139

Gnomad AMR exome

AF:

0.0116

Gnomad ASJ exome

AF:

0.0240

Gnomad EAS exome

AF:

0.00413

Gnomad FIN exome

AF:

0.000739

Gnomad NFE exome

AF:

0.00417

Gnomad OTH exome

AF:

0.0161

GnomAD4 exome

AF:

0.00960

AC:

14029

AN:

1461220

Hom.:

480

Cov.:

AF XY:

0.00980

AC XY:

7122

AN XY:

726944

show subpopulations

African (AFR)

AF:

0.143

AC:

4784

AN:

33448

American (AMR)

AF:

0.0124

AC:

554

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

611

AN:

26136

East Asian (EAS)

AF:

0.00186

AC:

AN:

39700

South Asian (SAS)

AF:

0.0329

AC:

2838

AN:

86220

European-Finnish (FIN)

AF:

0.000749

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.0165

AC:

AN:

5336

European-Non Finnish (NFE)

AF:

0.00356

AC:

3960

AN:

1111910

Other (OTH)

AF:

0.0179

AC:

1080

AN:

60330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

636

1273

1909

2546

3182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0446

AC:

6796

AN:

152302

Hom.:

420

Cov.:

AF XY:

0.0430

AC XY:

3203

AN XY:

74476

show subpopulations

African (AFR)

AF:

0.136

AC:

5643

AN:

41546

American (AMR)

AF:

0.0312

AC:

477

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.0311

AC:

108

AN:

3472

East Asian (EAS)

AF:

0.00424

AC:

AN:

5188

South Asian (SAS)

AF:

0.0371

AC:

179

AN:

4828

European-Finnish (FIN)

AF:

0.000377

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00388

AC:

264

AN:

68030

Other (OTH)

AF:

0.0416

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

300

599

899

1198

1498

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00641

Hom.:

Bravo

AF:

0.0509

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.135

AC:

593

ESP6500EA

AF:

0.00442

AC:

ExAC

AF:

0.0215

AC:

2611

Asia WGS

AF:

0.0670

AC:

234

AN:

3478

EpiCase

AF:

0.00420

EpiControl

AF:

0.00539

ClinVar

Significance: Benign

Submissions summary: Benign:6

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. -

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Nov 03, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2018

GeneDx

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

0.061

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.33

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.35

Eigen

Benign

-0.75

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.76

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.87

MutationAssessor

Benign

0.36

PhyloP100

0.48

PrimateAI

Benign

0.35

PROVEAN

Benign

0.10

REVEL

Benign

0.17

Sift

Benign

0.52

Sift4G

Benign

0.52

Polyphen

0.0

Vest4

0.11

MPC

0.046

ClinPred

0.00043

GERP RS

2.6

Varity_R

0.16

gMVP

0.45

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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rs73400312

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