rs143119940

Positions:

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 1P and 12B. PP3BP6_Very_StrongBS2

The NM_000170.3(GLDC):c.2203G>T(p.Val735Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0058 in 1,610,402 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0062 ( 20 hom., cov: 33)

Exomes 𝑓: 0.0058 ( 58 hom. )

Consequence

GLDC
NM_000170.3 missense, splice_region

Scores

Splicing: ADA: 0.9998

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 7.53

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:

GLDC (HGNC:):

GLDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -11 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: BayesDel_noAF, Cadd, dbscSNV1_ADA, dbscSNV1_RF, M_CAP, phyloP100way_vertebrate, REVEL [when BayesDel_addAF, FATHMM_MKL, MetaRNN, MutationAssessor, MutationTaster was below the threshold]

BP6

Variant 9-6554781-C-A is Benign according to our data. Variant chr9-6554781-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 367181.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6554781-C-A is described in Lovd as [Likely_benign].

BS2

High Homozygotes in GnomAd4 at 20 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 linkuse as main transcript	c.2203G>T	p.Val735Leu	missense_variant, splice_region_variant	19/25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 linkuse as main transcript	c.2203G>T	p.Val735Leu	missense_variant, splice_region_variant	19/25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.00623

AC:

949

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000868

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00647

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.0412

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00532

Gnomad OTH

AF:

0.00574

GnomAD3 exomes

AF:

0.00642

AC:

1575

AN:

245208

Hom.:

AF XY:

0.00638

AC XY:

844

AN XY:

132286

show subpopulations

Gnomad AFR exome

AF:

0.00115

Gnomad AMR exome

AF:

0.00217

Gnomad ASJ exome

AF:

0.000101

Gnomad EAS exome

AF:

0.000110

Gnomad SAS exome

AF:

0.000170

Gnomad FIN exome

AF:

0.0387

Gnomad NFE exome

AF:

0.00560

Gnomad OTH exome

AF:

0.00635

GnomAD4 exome

AF:

0.00575

AC:

8390

AN:

1458034

Hom.:

Cov.:

AF XY:

0.00568

AC XY:

4120

AN XY:

725014

show subpopulations

Gnomad4 AFR exome

AF:

0.000599

Gnomad4 AMR exome

AF:

0.00297

Gnomad4 ASJ exome

AF:

0.000154

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.000187

Gnomad4 FIN exome

AF:

0.0332

Gnomad4 NFE exome

AF:

0.00555

Gnomad4 OTH exome

AF:

0.00473

GnomAD4 genome

AF:

0.00623

AC:

949

AN:

152368

Hom.:

Cov.:

AF XY:

0.00721

AC XY:

537

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000866

Gnomad4 AMR

AF:

0.00647

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.0412

Gnomad4 NFE

AF:

0.00532

Gnomad4 OTH

AF:

0.00568

Alfa

AF:

0.00455

Hom.:

Bravo

AF:

0.00398

TwinsUK

AF:

0.00431

AC:

ALSPAC

AF:

0.00675

AC:

ESP6500AA

AF:

0.00136

AC:

ESP6500EA

AF:

0.00291

AC:

ExAC

AF:

0.00545

AC:

662

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 06, 2017	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2024	GLDC: BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

Glycine encephalopathy

Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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	Jan 31, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 08, 2020	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.0014

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.68

D;.;.

Eigen

Uncertain

0.19

Eigen_PC

Uncertain

0.30

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

D;D;D

M_CAP

Pathogenic

0.35

MetaRNN

Benign

0.011

T;T;T

MetaSVM

Uncertain

0.63

MutationAssessor

Benign

1.6

L;.;.

PrimateAI

Uncertain

0.73

PROVEAN

Uncertain

-2.6

D;.;.

REVEL

Pathogenic

0.85

Sift

Uncertain

0.0070

D;.;.

Sift4G

Uncertain

0.0090

D;.;.

Polyphen

0.21

B;.;.

Vest4

0.92

MutPred

0.67

Gain of sheet (P = 0.1945);.;.;

MVP

0.98

MPC

0.17

ClinPred

0.026

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.75

gMVP

0.90

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.97

SpliceAI score (max)

0.42

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.42

Position offset: 0

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