chr9-6620216-C-T

Position:

• chr9-6620216-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.438G>A​(p.Thr146=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0828 in 1,612,532 control chromosomes in the GnomAD database, including 6,575 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (386 hom., cov: 32)
  • Exomes 𝑓: 0.085 (6189 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 9-6620216-C-T is Benign according to our data. Variant chr9-6620216-C-T is described in ClinVar as [Benign]. Clinvar id is 367204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6620216-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=0.822 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0904 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3	c.438G>A	p.Thr146=	synonymous_variant	3/25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.438G>A	p.Thr146=	synonymous_variant	3/25	1	NM_000170.3	ENSP00000370737	P1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9117 AN: 152066 Hom.: 385 Cov.: 32

Gnomad AFR AF: 0.0159

Gnomad AMI AF: 0.0362

Gnomad AMR AF: 0.0448

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0158

Gnomad FIN AF: 0.110

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0923

Gnomad OTH AF: 0.0526

GnomAD3 exomes AF: 0.0612 AC: 15396 AN: 251478 Hom.: 700 AF XY: 0.0603 AC XY: 8198 AN XY: 135910

Gnomad AFR exome AF: 0.0145

Gnomad AMR exome AF: 0.0282

Gnomad ASJ exome AF: 0.0319

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.0166

Gnomad FIN exome AF: 0.119

Gnomad NFE exome AF: 0.0914

Gnomad OTH exome AF: 0.0611

GnomAD4 exome AF: 0.0852 AC: 124432 AN: 1460348 Hom.: 6189 Cov.: 32 AF XY: 0.0830 AC XY: 60302 AN XY: 726584

Gnomad4 AFR exome AF: 0.0126

Gnomad4 AMR exome AF: 0.0298

Gnomad4 ASJ exome AF: 0.0313

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0178

Gnomad4 FIN exome AF: 0.118

Gnomad4 NFE exome AF: 0.0989

Gnomad4 OTH exome AF: 0.0682

GnomAD4 genome AF: 0.0599 AC: 9117 AN: 152184 Hom.: 386 Cov.: 32 AF XY: 0.0590 AC XY: 4388 AN XY: 74406

Gnomad4 AFR AF: 0.0158

Gnomad4 AMR AF: 0.0446

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0158

Gnomad4 FIN AF: 0.110

Gnomad4 NFE AF: 0.0923

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0642 Hom.: 150

Bravo AF: 0.0538

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.0810

EpiControl AF: 0.0787

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Non-ketotic hyperglycinemia Benign:3

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Nov 22, 2019	- -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2018	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Apr 14, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.2
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs13289273; hg19: chr9-6620216; COSMIC: COSV58680526;