9-6532544-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000170.3(GLDC):c.*473C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.68 in 156,572 control chromosomes in the GnomAD database, including 36,656 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.68 (35599 hom., cov: 29)
  • Exomes 𝑓: 0.62 (1057 hom.)
• Consequence: GLDC NM_000170.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.397

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-6532544-G-A is Benign according to our data. Variant chr9-6532544-G-A is described in ClinVar as [Benign]. Clinvar id is 367164.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.927 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.*473C>T		3_prime_UTR_variant	25/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.*473C>T		3_prime_UTR_variant	25/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.681 AC: 103052 AN: 151218 Hom.: 35575 Cov.: 29

Gnomad AFR AF: 0.705

Gnomad AMI AF: 0.395

Gnomad AMR AF: 0.721

Gnomad ASJ AF: 0.627

Gnomad EAS AF: 0.949

Gnomad SAS AF: 0.707

Gnomad FIN AF: 0.736

Gnomad MID AF: 0.652

Gnomad NFE AF: 0.636

Gnomad OTH AF: 0.641

GnomAD4 exome AF: 0.623 AC: 3265 AN: 5244 Hom.: 1057 Cov.: 0 AF XY: 0.624 AC XY: 1723 AN XY: 2760

Gnomad4 AFR exome AF: 0.643

Gnomad4 AMR exome AF: 0.708

Gnomad4 ASJ exome AF: 0.458

Gnomad4 EAS exome AF: 0.917

Gnomad4 SAS exome AF: 0.603

Gnomad4 FIN exome AF: 0.707

Gnomad4 NFE exome AF: 0.570

Gnomad4 OTH exome AF: 0.641

GnomAD4 genome AF: 0.682 AC: 103131 AN: 151328 Hom.: 35599 Cov.: 29 AF XY: 0.688 AC XY: 50846 AN XY: 73894

Gnomad4 AFR AF: 0.704

Gnomad4 AMR AF: 0.722

Gnomad4 ASJ AF: 0.627

Gnomad4 EAS AF: 0.949

Gnomad4 SAS AF: 0.706

Gnomad4 FIN AF: 0.736

Gnomad4 NFE AF: 0.636

Gnomad4 OTH AF: 0.641

Alfa AF: 0.650 Hom.: 9777

Bravo AF: 0.681

Asia WGS AF: 0.809 AC: 2809 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Non-ketotic hyperglycinemia Benign:1

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
Cadd	Benign	1.8
Dann	Benign	0.58

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: rs1061407; hg19: chr9-6532544;