rs2228098

Positions:

• chr9-6533010-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000170.3(GLDC):​c.*7G>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.646 in 1,595,334 control chromosomes in the GnomAD database, including 337,953 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.67 (34684 hom., cov: 31)
  • Exomes 𝑓: 0.64 (303269 hom.)
• Consequence: GLDC NM_000170.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.367

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 9-6533010-C-G is Benign according to our data. Variant chr9-6533010-C-G is described in ClinVar as [Benign]. Clinvar id is 255452.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6533010-C-G is described in Lovd as [Benign]. Variant chr9-6533010-C-G is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.*7G>C		3_prime_UTR_variant	25/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.*7G>C		3_prime_UTR_variant	25/25	1	NM_000170.3	ENSP00000370737	P1

Frequencies

GnomAD3 genomes AF: 0.671 AC: 101921 AN: 151884 Hom.: 34653 Cov.: 31

Gnomad AFR AF: 0.717

Gnomad AMI AF: 0.485

Gnomad AMR AF: 0.709

Gnomad ASJ AF: 0.636

Gnomad EAS AF: 0.947

Gnomad SAS AF: 0.715

Gnomad FIN AF: 0.649

Gnomad MID AF: 0.674

Gnomad NFE AF: 0.619

Gnomad OTH AF: 0.647

GnomAD3 exomes AF: 0.691 AC: 173606 AN: 251322 Hom.: 61347 AF XY: 0.681 AC XY: 92567 AN XY: 135832

Gnomad AFR exome AF: 0.722

Gnomad AMR exome AF: 0.797

Gnomad ASJ exome AF: 0.650

Gnomad EAS exome AF: 0.950

Gnomad SAS exome AF: 0.714

Gnomad FIN exome AF: 0.661

Gnomad NFE exome AF: 0.617

Gnomad OTH exome AF: 0.650

GnomAD4 exome AF: 0.644 AC: 929353 AN: 1443332 Hom.: 303269 Cov.: 28 AF XY: 0.644 AC XY: 463251 AN XY: 719074

Gnomad4 AFR exome AF: 0.722

Gnomad4 AMR exome AF: 0.786

Gnomad4 ASJ exome AF: 0.648

Gnomad4 EAS exome AF: 0.955

Gnomad4 SAS exome AF: 0.715

Gnomad4 FIN exome AF: 0.664

Gnomad4 NFE exome AF: 0.617

Gnomad4 OTH exome AF: 0.653

GnomAD4 genome AF: 0.671 AC: 102005 AN: 152002 Hom.: 34684 Cov.: 31 AF XY: 0.675 AC XY: 50168 AN XY: 74278

Gnomad4 AFR AF: 0.717

Gnomad4 AMR AF: 0.709

Gnomad4 ASJ AF: 0.636

Gnomad4 EAS AF: 0.947

Gnomad4 SAS AF: 0.715

Gnomad4 FIN AF: 0.649

Gnomad4 NFE AF: 0.619

Gnomad4 OTH AF: 0.646

Alfa AF: 0.632 Hom.: 9799

Bravo AF: 0.676

Asia WGS AF: 0.822 AC: 2858 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 20, 2017	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Non-ketotic hyperglycinemia Benign:4

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 10, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	1.8
DANN	Benign	0.60

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: rs2228098; hg19: chr9-6533010; COSMIC: COSV58684284;