rs535143891

Positions:

• chr9-6645448-C-A
• chr9-6645448-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000170.3(GLDC):​c.52G>T​(p.Gly18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 1,259,152 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0066 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (76 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:8
• Conservation: PhyloP100: 0.822

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070572793).
• BP6: Variant 9-6645448-C-A is Benign according to our data. Variant chr9-6645448-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 367208.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=3, Benign=2}. Variant chr9-6645448-C-A is described in Lovd as [Benign]. Variant chr9-6645448-C-A is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.52G>T	p.Gly18Cys	missense_variant	1/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.52G>T	p.Gly18Cys	missense_variant	1/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1000 AN: 151778 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00938

Gnomad OTH AF: 0.00576

GnomAD3 exomes AF: 0.0155 AC: 72 AN: 4648 Hom.: 3 AF XY: 0.0152 AC XY: 43 AN XY: 2834

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00711

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.00926

GnomAD4 exome AF: 0.00952 AC: 10545 AN: 1107266 Hom.: 76 Cov.: 31 AF XY: 0.00945 AC XY: 5027 AN XY: 531864

Gnomad4 AFR exome AF: 0.00156

Gnomad4 AMR exome AF: 0.00320

Gnomad4 ASJ exome AF: 0.000874

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00364

Gnomad4 FIN exome AF: 0.0222

Gnomad4 NFE exome AF: 0.0101

Gnomad4 OTH exome AF: 0.00692

GnomAD4 genome AF: 0.00658 AC: 1000 AN: 151886 Hom.: 2 Cov.: 32 AF XY: 0.00696 AC XY: 517 AN XY: 74254

Gnomad4 AFR AF: 0.00173

Gnomad4 AMR AF: 0.00551

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00373

Gnomad4 FIN AF: 0.0156

Gnomad4 NFE AF: 0.00938

Gnomad4 OTH AF: 0.00570

Alfa AF: 0.00309 Hom.: 0

Bravo AF: 0.00531

ExAC AF: 0.00274 AC: 24

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:8

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:1 Benign:3

Uncertain significance, criteria provided, single submitter	clinical testing	Elsea Laboratory, Baylor College of Medicine	Apr 01, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, no assertion criteria provided	clinical testing	Natera, Inc.	Dec 09, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	GLDC: PP3, BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 04, 2018	This variant is associated with the following publications: (PMID: 22171071) -

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Oct 30, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0071	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.74	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.48
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.38
MPC		0.31
ClinPred		0.051	T
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.48

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: rs535143891; hg19: chr9-6645448; COSMIC: COSV58681545; COSMIC: COSV58681545;