rs12004478

Variant names:

• chr9-6581660-T-C
• rs12004478
• NM_000170.3:c.1850+5481A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000170.3(GLDC):​c.1850+5481A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.274 in 152,020 control chromosomes in the GnomAD database, including 5,845 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.27 (5845 hom., cov: 32)
• Consequence: GLDC NM_000170.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.04
• Publications: 4 publications found

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 Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Myriad Women’s Health, Labcorp Genetics (formerly Invitae), ClinGen
• glycine encephalopathy 1

  Inheritance: AR Classification: DEFINITIVE Submitted by: G2P
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.97).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.315 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.1850+5481A>G		intron_variant	Intron 15 of 24	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.1850+5481A>G		intron_variant	Intron 15 of 24	1	NM_000170.3	ENSP00000370737.4

Frequencies

GnomAD3 genomes AF: 0.274 AC: 41621 AN: 151902 Hom.: 5850 Cov.: 32

Gnomad AFR AF: 0.275

Gnomad AMI AF: 0.280

Gnomad AMR AF: 0.323

Gnomad ASJ AF: 0.218

Gnomad EAS AF: 0.169

Gnomad SAS AF: 0.280

Gnomad FIN AF: 0.259

Gnomad MID AF: 0.282

Gnomad NFE AF: 0.275

Gnomad OTH AF: 0.281

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.274 AC: 41624 AN: 152020 Hom.: 5845 Cov.: 32 AF XY: 0.274 AC XY: 20358 AN XY: 74316

African (AFR) AF: 0.275 AC: 11390 AN: 41452

American (AMR) AF: 0.322 AC: 4922 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.218 AC: 756 AN: 3472

East Asian (EAS) AF: 0.169 AC: 873 AN: 5174

South Asian (SAS) AF: 0.280 AC: 1351 AN: 4824

European-Finnish (FIN) AF: 0.259 AC: 2735 AN: 10550

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.275 AC: 18669 AN: 67964

Other (OTH) AF: 0.282 AC: 595 AN: 2108

Alfa AF: 0.272 Hom.: 795

Bravo AF: 0.278

Asia WGS AF: 0.214 AC: 746 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	6.3
DANN	Benign	0.61
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs12004478; hg19: chr9-6581660;