Genetic Variant GLDC:p.Met107Leu (chr9-6644629-T-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_000170.3(GLDC):c.319A>T(p.Met107Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict 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. M107V) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.01

Publications

7 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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.10693869).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.319A>T	p.Met107Leu	missense_variant	Exon 2 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.319A>T	p.Met107Leu	missense_variant	Exon 2 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251404

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1459560

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726306

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000299

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26126

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86228

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53368

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5764

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1109912

Other (OTH)

AF:

0.00

AC:

AN:

60308

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.082

BayesDel_noAF

Benign

-0.17

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.32

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.53

FATHMM_MKL

Uncertain

0.85

LIST_S2

Benign

0.73

M_CAP

Benign

0.041

MetaRNN

Benign

0.11

MetaSVM

Benign

-0.53

MutationAssessor

Benign

-2.7

PhyloP100

4.0

PrimateAI

Uncertain

0.50

PROVEAN

Benign

0.80

REVEL

Uncertain

0.32

Sift

Benign

1.0

Sift4G

Benign

1.0

Polyphen

0.0

Vest4

0.34

MutPred

0.48

Loss of methylation at K102 (P = 0.065);

MVP

0.61

MPC

0.044

ClinPred

0.16

GERP RS

2.2

Varity_R

0.47

gMVP

0.71

Mutation Taster

=85/15

polymorphism

(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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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over