chr9-6589250-G-C

Variant names:

• chr9-6589250-G-C
• rs557412758
• NM_000170.3:c.1525C>G

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 4P and 12B. PS3 BP4_Strong BS1 BS2

The NM_000170.3(GLDC):​c.1525C>G​(p.Pro509Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000161 in 1,611,172 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). ClinVar reports functional evidence for this variant: "SCV005373530: Published functional studies demonstrate that this variant resulted in a significant reduction in GLDC activity compared to wild-type (Narisawa A, et al., 2012).".

• Frequency:
  • Genomes: 𝑓 0.000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00017 (3 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:7
• Conservation: PhyloP100: 1.05
• 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 -8 ACMG points.

• PS3: PS3 evidence extracted from ClinVar submissions: SCV005373530: Published functional studies demonstrate that this variant resulted in a significant reduction in GLDC activity compared to wild-type (Narisawa A, et al., 2012).
• BP4: Computational evidence support a benign effect (MetaRNN=0.025778532).
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000171 (249/1459024) while in subpopulation SAS AF = 0.00275 (237/86192). AF 95% confidence interval is 0.00246. There are 3 homozygotes in GnomAdExome4. There are 161 alleles in the male GnomAdExome4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR,Unknown gene

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.1525C>G	p.Pro509Ala	missense	Exon 12 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.1525C>G	p.Pro509Ala	missense	Exon 12 of 25	ENSP00000370737.4	P23378
	GLDC	ENST00000639443.1	TSL:1	n.1093C>G		non_coding_transcript_exon	Exon 8 of 21
	GLDC	ENST00000920236.1		c.1525C>G	p.Pro509Ala	missense	Exon 12 of 25	ENSP00000590295.1

Frequencies

GnomAD3 genomes AF: 0.0000658 AC: 10 AN: 152030 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000298 AC: 75 AN: 251472 AF XY: 0.000412

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1459024 Hom.: 3 Cov.: 28 AF XY: 0.000222 AC XY: 161 AN XY: 726098

African (AFR) AF: 0.00 AC: 0 AN: 33428

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.00275 AC: 237 AN: 86192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1109404

Other (OTH) AF: 0.000133 AC: 8 AN: 60298

GnomAD4 genome AF: 0.0000657 AC: 10 AN: 152148 Hom.: 0 Cov.: 32 AF XY: 0.0000807 AC XY: 6 AN XY: 74384

African (AFR) AF: 0.00 AC: 0 AN: 41496

American (AMR) AF: 0.00 AC: 0 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10580

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68012

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000288 AC: 35

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	0.040
CADD	Benign	14
DANN	Benign	0.70
DEOGEN2	Benign	0.41	T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.31
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.026	T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	-0.090	N
PhyloP100		1.1
PrimateAI	Benign	0.28	T
PROVEAN	Benign	0.22	N
REVEL	Uncertain	0.62
Sift	Benign	0.28	T
Sift4G	Benign	0.076	T
Polyphen		0.0	B
Vest4		0.43
MVP		0.95
MPC		0.045
ClinPred		0.035	T
GERP RS		4.5
Varity_R		0.081
gMVP		0.62
Mutation Taster		=27/73	disease causing

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: rs557412758; hg19: chr9-6589250;