9-6550851-C-T

Position:

• chr9-6550851-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PM5 PP3

The NM_000170.3(GLDC):​c.2521G>A​(p.Ala841Thr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic 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. A841P) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.32

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 Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 uncertain in NM_000170.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr9-6550851-C-G is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.746

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.2521G>A	p.Ala841Thr	missense_variant	21/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.2521G>A	p.Ala841Thr	missense_variant	21/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.51	D;.;.;.
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Pathogenic	0.98	D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.75	D;D;D;D
MetaSVM	Uncertain	0.48	D
MutationAssessor	Pathogenic	3.3	M;.;.;.
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	-1.6	N;.;.;.
REVEL	Uncertain	0.62
Sift	Benign	0.038	D;.;.;.
Sift4G	Uncertain	0.022	D;.;.;.
Polyphen		0.44	B;.;.;.
Vest4		0.72
MutPred		0.53		Loss of methylation at R843 (P = 0.0886);.;.;.;
MVP		0.92
MPC		0.10
ClinPred		0.98	D
GERP RS		4.7
Varity_R		0.44
gMVP		0.85

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

LitVar

Other links and lift over

dbSNP: rs386833562; hg19: chr9-6550851;