rs73400312

chr9-6592868-G-Cchr9-6592868-G-T

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000170.3(GLDC):c.1384C>G(p.Leu462Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0129 in 1,613,522 control chromosomes in the GnomAD database, including 900 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. L462L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.045 (420 hom., cov: 32)
  • Exomes 𝑓: 0.0096 (480 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.477

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 -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000170.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.0021384656).
• BP6: Variant 9-6592868-G-C is Benign according to our data. Variant chr9-6592868-G-C is described in ClinVar as [Benign]. Clinvar id is 367193.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6592868-G-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.1384C>G	p.Leu462Val	missense_variant	10/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.1384C>G	p.Leu462Val	missense_variant	10/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.0445 AC: 6773 AN: 152184 Hom.: 418 Cov.: 32

Gnomad AFR AF: 0.136

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0312

Gnomad ASJ AF: 0.0311

Gnomad EAS AF: 0.00423

Gnomad SAS AF: 0.0375

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.00388

Gnomad OTH AF: 0.0368

GnomAD3 exomes AF: 0.0187 AC: 4701 AN: 251430 Hom.: 199 AF XY: 0.0174 AC XY: 2363 AN XY: 135888

Gnomad AFR exome AF: 0.139

Gnomad AMR exome AF: 0.0116

Gnomad ASJ exome AF: 0.0240

Gnomad EAS exome AF: 0.00413

Gnomad SAS exome AF: 0.0372

Gnomad FIN exome AF: 0.000739

Gnomad NFE exome AF: 0.00417

Gnomad OTH exome AF: 0.0161

GnomAD4 exome AF: 0.00960 AC: 14029 AN: 1461220 Hom.: 480 Cov.: 31 AF XY: 0.00980 AC XY: 7122 AN XY: 726944

Gnomad4 AFR exome AF: 0.143

Gnomad4 AMR exome AF: 0.0124

Gnomad4 ASJ exome AF: 0.0234

Gnomad4 EAS exome AF: 0.00186

Gnomad4 SAS exome AF: 0.0329

Gnomad4 FIN exome AF: 0.000749

Gnomad4 NFE exome AF: 0.00356

Gnomad4 OTH exome AF: 0.0179

GnomAD4 genome AF: 0.0446 AC: 6796 AN: 152302 Hom.: 420 Cov.: 32 AF XY: 0.0430 AC XY: 3203 AN XY: 74476

Gnomad4 AFR AF: 0.136

Gnomad4 AMR AF: 0.0312

Gnomad4 ASJ AF: 0.0311

Gnomad4 EAS AF: 0.00424

Gnomad4 SAS AF: 0.0371

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.00388

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.00641 Hom.: 5

Bravo AF: 0.0509

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00389 AC: 15

ESP6500AA AF: 0.135 AC: 593

ESP6500EA AF: 0.00442 AC: 38

ExAC AF: 0.0215 AC: 2611

Asia WGS AF: 0.0670 AC: 234 AN: 3478

EpiCase AF: 0.00420

EpiControl AF: 0.00539

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 17, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 03, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.061
BayesDel_addAF	Benign	-0.47	T
BayesDel_noAF	Benign	-0.33
Cadd	Benign	14
Dann	Benign	0.93
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.75
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.25	N
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0021	T
MetaSVM	Benign	-0.87	T
MutationAssessor	Benign	0.36	N
MutationTaster	Benign	0.51	N
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.10	N
REVEL	Benign	0.17
Sift	Benign	0.52	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.11
MPC		0.046
ClinPred		0.00043	T
GERP RS		2.6
Varity_R		0.16
gMVP		0.45

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs73400312; hg19: chr9-6592868;