rs751588571

Positions:

• chr9-6592192-T-C
• chr9-6592192-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000170.3(GLDC):​c.1433A>G​(p.Glu478Gly) variant causes a missense change. The variant allele was found at a frequency of 0.00000206 in 1,455,240 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. E478A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.09

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.1433A>G	p.Glu478Gly	missense_variant	11/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.1433A>G	p.Glu478Gly	missense_variant	11/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251048 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135730

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 SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000206 AC: 3 AN: 1455240 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 724446

Gnomad4 AFR exome AF: 0.0000300

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.37
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.73	D
Eigen	Benign	0.075
Eigen_PC	Uncertain	0.22
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.68	D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Uncertain	2.0	M
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.4	D
REVEL	Pathogenic	0.72
Sift	Benign	0.38	T
Sift4G	Benign	0.50	T
Polyphen		0.014	B
Vest4		0.69
MutPred		0.38		Loss of stability (P = 0.0559);
MVP		0.99
MPC		0.33
ClinPred		0.96	D
GERP RS		5.1
Varity_R		0.91
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs751588571; hg19: chr9-6592192;