Genetic Variant GLDC:p.Gly18Ser (chr9-6645448-C-T) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_000170.3(GLDC):c.52G>A(p.Gly18Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G18C) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.822

Publications

4 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:

LINC02851 (HGNC:):

LINC02851 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.27693114).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.52G>A	p.Gly18Ser	missense	Exon 1 of 25	NP_000161.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GLDC	ENST00000321612.8	TSL:1 MANE Select	c.52G>A	p.Gly18Ser	missense	Exon 1 of 25	ENSP00000370737.4
GLDC	ENST00000920236.1		c.52G>A	p.Gly18Ser	missense	Exon 1 of 25	ENSP00000590295.1
GLDC	ENST00000953081.1		c.52G>A	p.Gly18Ser	missense	Exon 1 of 26	ENSP00000623139.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1107282

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

531874

African (AFR)

AF:

0.00

AC:

AN:

22414

American (AMR)

AF:

0.00

AC:

AN:

8114

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

13726

East Asian (EAS)

AF:

0.00

AC:

AN:

25090

South Asian (SAS)

AF:

0.00

AC:

AN:

25570

European-Finnish (FIN)

AF:

0.00

AC:

AN:

23926

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2910

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

941298

Other (OTH)

AF:

0.00

AC:

AN:

44234

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.079

BayesDel_noAF

Benign

-0.12

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.65

FATHMM_MKL

Benign

0.24

LIST_S2

Benign

0.45

M_CAP

Pathogenic

0.95

MetaRNN

Benign

0.28

MetaSVM

Uncertain

0.41

MutationAssessor

Benign

0.0

PhyloP100

0.82

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

0.42

REVEL

Uncertain

0.35

Sift

Benign

0.54

Sift4G

Benign

0.31

Polyphen

0.0060

Vest4

0.27

MutPred

0.31

Gain of glycosylation at G18 (P = 0.0036)

MVP

0.92

MPC

0.26

ClinPred

0.43

GERP RS

3.6

PromoterAI

0.038

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.063

gMVP

0.39

Mutation Taster

=95/5

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over