NM_000170.3:c.438G>A

Variant names:

• chr9-6620216-C-T
• rs13289273
• NM_000170.3:c.438G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000170.3(GLDC):​c.438G>A​(p.Thr146Thr) 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 (★★). Synonymous variant affecting the same amino acid position (i.e. T146T) has been classified as Likely 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
• Publications: 7 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 -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 VariationId is 367204.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.438G>A	p.Thr146Thr	synonymous	Exon 3 of 25	NP_000161.2	P23378

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.438G>A	p.Thr146Thr	synonymous	Exon 3 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000920236.1		c.438G>A	p.Thr146Thr	synonymous	Exon 3 of 25	ENSP00000590295.1
	GLDC	ENST00000953081.1		c.438G>A	p.Thr146Thr	synonymous	Exon 3 of 26	ENSP00000623139.1

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

GnomAD2 exomes AF: 0.0612 AC: 15396 AN: 251478 AF XY: 0.0603

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 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

African (AFR) AF: 0.0126 AC: 420 AN: 33466

American (AMR) AF: 0.0298 AC: 1331 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0313 AC: 818 AN: 26134

East Asian (EAS) AF: 0.000101 AC: 4 AN: 39696

South Asian (SAS) AF: 0.0178 AC: 1538 AN: 86220

European-Finnish (FIN) AF: 0.118 AC: 6315 AN: 53414

Middle Eastern (MID) AF: 0.0129 AC: 70 AN: 5438

European-Non Finnish (NFE) AF: 0.0989 AC: 109823 AN: 1110920

Other (OTH) AF: 0.0682 AC: 4113 AN: 60338

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

African (AFR) AF: 0.0158 AC: 657 AN: 41538

American (AMR) AF: 0.0446 AC: 682 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.0340 AC: 118 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4818

European-Finnish (FIN) AF: 0.110 AC: 1162 AN: 10582

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0923 AC: 6276 AN: 67996

Other (OTH) AF: 0.0520 AC: 110 AN: 2114

Alfa AF: 0.0677 Hom.: 229

Bravo AF: 0.0538

Asia WGS AF: 0.00866 AC: 31 AN: 3478

EpiCase AF: 0.0810

EpiControl AF: 0.0787

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycine encephalopathy (3)
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	7.2
DANN	Benign	0.67
PhyloP100		0.82
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs13289273; hg19: chr9-6620216; COSMIC: COSV58680526;