rs12004164

Variant names:

• chr9-6606639-A-G
• rs12004164
• NM_000170.3:c.666T>C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.666T>C​(p.Asp222Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00557 in 1,608,470 control chromosomes in the GnomAD database, including 274 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (141 hom., cov: 32)
  • Exomes 𝑓: 0.0036 (133 hom.)
• Consequence: GLDC NM_000170.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.874

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.57).
• BP6: Variant 9-6606639-A-G is Benign according to our data. Variant chr9-6606639-A-G is described in ClinVar as [Benign]. Clinvar id is 367201.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.874 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0776 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.666T>C	p.Asp222Asp	synonymous_variant	Exon 5 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.666T>C	p.Asp222Asp	synonymous_variant	Exon 5 of 25	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes AF: 0.0242 AC: 3688 AN: 152166 Hom.: 137 Cov.: 32

Gnomad AFR AF: 0.0796

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0129

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00269

Gnomad SAS AF: 0.0215

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000573

Gnomad OTH AF: 0.0158

GnomAD3 exomes AF: 0.00946 AC: 2380 AN: 251462 Hom.: 60 AF XY: 0.00900 AC XY: 1223 AN XY: 135912

Gnomad AFR exome AF: 0.0815

Gnomad AMR exome AF: 0.00480

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.00245

Gnomad SAS exome AF: 0.0239

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000668

Gnomad OTH exome AF: 0.00619

GnomAD4 exome AF: 0.00360 AC: 5238 AN: 1456186 Hom.: 133 Cov.: 28 AF XY: 0.00384 AC XY: 2780 AN XY: 724890

Gnomad4 AFR exome AF: 0.0730

Gnomad4 AMR exome AF: 0.00552

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.000933

Gnomad4 SAS exome AF: 0.0191

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000383

Gnomad4 OTH exome AF: 0.00771

GnomAD4 genome AF: 0.0244 AC: 3715 AN: 152284 Hom.: 141 Cov.: 32 AF XY: 0.0244 AC XY: 1818 AN XY: 74478

Gnomad4 AFR AF: 0.0799

Gnomad4 AMR AF: 0.0129

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00270

Gnomad4 SAS AF: 0.0209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000573

Gnomad4 OTH AF: 0.0203

Alfa AF: 0.0113 Hom.: 33

Bravo AF: 0.0273

Asia WGS AF: 0.0440 AC: 154 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycine encephalopathy Benign:3

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 10, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Jun 29, 2017

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

GLDC-related disorder Benign:1

Feb 28, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.57
CADD	Benign	3.2
DANN	Benign	0.51
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs12004164; hg19: chr9-6606639;