chr9-6595046-C-T

Position:

• chr9-6595046-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_000170.3(GLDC):​c.1229G>A​(p.Arg410Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00114 in 1,611,492 control chromosomes in the GnomAD database, including 21 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 0.0026 (6 hom., cov: 33)
  • Exomes 𝑓: 0.00098 (15 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:10
• Conservation: PhyloP100: 7.20

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP6: Variant 9-6595046-C-T is Benign according to our data. Variant chr9-6595046-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 225378.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=7}. Variant chr9-6595046-C-T is described in Lovd as [Benign]. Variant chr9-6595046-C-T is described in Lovd as [Likely_benign]. Variant chr9-6595046-C-T is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0026 (396/152280) while in subpopulation AMR AF= 0.022 (336/15300). AF 95% confidence interval is 0.02. There are 6 homozygotes in gnomad4. There are 200 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.1229G>A	p.Arg410Lys	missense_variant	9/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.1229G>A	p.Arg410Lys	missense_variant	9/25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 398 AN: 152162 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.000748

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0221

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00385 AC: 966 AN: 251170 Hom.: 14 AF XY: 0.00277 AC XY: 376 AN XY: 135750

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.0262

Gnomad ASJ exome AF: 0.000298

Gnomad EAS exome AF: 0.000924

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00473

GnomAD4 exome AF: 0.000985 AC: 1437 AN: 1459212 Hom.: 15 Cov.: 30 AF XY: 0.000804 AC XY: 584 AN XY: 726126

Gnomad4 AFR exome AF: 0.000359

Gnomad4 AMR exome AF: 0.0274

Gnomad4 ASJ exome AF: 0.000345

Gnomad4 EAS exome AF: 0.00116

Gnomad4 SAS exome AF: 0.0000232

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000252

Gnomad4 OTH exome AF: 0.00187

GnomAD4 genome AF: 0.00260 AC: 396 AN: 152280 Hom.: 6 Cov.: 33 AF XY: 0.00269 AC XY: 200 AN XY: 74476

Gnomad4 AFR AF: 0.000746

Gnomad4 AMR AF: 0.0220

Gnomad4 ASJ AF: 0.000576

Gnomad4 EAS AF: 0.00193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.000736 Hom.: 1

Bravo AF: 0.00475

ESP6500AA AF: 0.00113 AC: 5

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00285 AC: 346

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:10

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Glycine encephalopathy Uncertain:1 Benign:5

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 28, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Mendelics	Jul 13, 2023	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Jan 09, 2020	- -
Benign, criteria provided, single submitter	research	Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard	-	The homozygous p.Arg410Lys variant in GLDC has been identified in an individual with non-ketotic hyperglycinaemia (PMID: 12126939), but has also been identified in >2% of Latino chromosomes and 8 homozygotes by ExAC (http://gnomad.broadinstitute.org/). In summary, this variant meets criteria to be classified as benign for autosomal recessive non-ketotic hyperglycinaemia. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, criteria provided, single submitter	reference population	Soonchunhyang University Bucheon Hospital, Soonchunhyang University Medical Center	Mar 18, 2016	- -

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 02, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 20, 2018	This variant is associated with the following publications: (PMID: 29153744, 27535533, 27362913, 12126939) -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	GLDC: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.017	T
BayesDel_noAF	Pathogenic	0.22
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.72	D;.
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D;D
MetaRNN	Benign	0.011	T;T
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.0	M;.
PrimateAI	Uncertain	0.64	T
PROVEAN	Uncertain	-2.4	N;.
REVEL	Pathogenic	0.76
Sift	Benign	0.053	T;.
Sift4G	Benign	0.086	T;.
Polyphen		0.39	B;.
Vest4		0.78
MVP		0.97
MPC		0.10
ClinPred		0.059	T
GERP RS		4.7
Varity_R		0.79
gMVP		0.83

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.35		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.35		Position offset: -1

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

Publications

LitVar

Other links and lift over

dbSNP: rs144090917; hg19: chr9-6595046;