rs1821892

Variant names:

• chr9-6616648-C-G
• rs1821892
• NM_000170.3:c.470+3536G>C

Variant summary

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

The NM_000170.3(GLDC):​c.470+3536G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 152,126 control chromosomes in the GnomAD database, including 4,636 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 0.23 (4636 hom., cov: 32)
• Consequence: GLDC NM_000170.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.374
• Publications: 5 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.470+3536G>C		intron	N/A	NP_000161.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.470+3536G>C		intron	N/A	ENSP00000370737.4
	GLDC	ENST00000639840.1	TSL:5	c.176+3536G>C		intron	N/A	ENSP00000491161.1
	GLDC	ENST00000639020.1	TSL:3	c.65+3536G>C		intron	N/A	ENSP00000491392.1

Frequencies

GnomAD3 genomes AF: 0.228 AC: 34706 AN: 152008 Hom.: 4620 Cov.: 32

Gnomad AFR AF: 0.367

Gnomad AMI AF: 0.124

Gnomad AMR AF: 0.230

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.224

Gnomad FIN AF: 0.185

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.141

Gnomad OTH AF: 0.216

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

GnomAD4 genome AF: 0.229 AC: 34765 AN: 152126 Hom.: 4636 Cov.: 32 AF XY: 0.231 AC XY: 17191 AN XY: 74374

African (AFR) AF: 0.367 AC: 15230 AN: 41502

American (AMR) AF: 0.230 AC: 3516 AN: 15256

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 548 AN: 3472

East Asian (EAS) AF: 0.426 AC: 2206 AN: 5180

South Asian (SAS) AF: 0.223 AC: 1075 AN: 4814

European-Finnish (FIN) AF: 0.185 AC: 1956 AN: 10574

Middle Eastern (MID) AF: 0.139 AC: 41 AN: 294

European-Non Finnish (NFE) AF: 0.141 AC: 9620 AN: 68010

Other (OTH) AF: 0.218 AC: 460 AN: 2112

Alfa AF: 0.184 Hom.: 390

Bravo AF: 0.241

Asia WGS AF: 0.288 AC: 1000 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.36
DANN	Benign	0.54
PhyloP100		-0.37
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: rs1821892; hg19: chr9-6616648;