rs535143891

Variant names:

• chr9-6645448-C-A
• rs535143891
• NM_000170.3:c.52G>T

Your query was ambiguous. Multiple possible variants found:

• chr9-6645448-C-A
• chr9-6645448-C-T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_000170.3(GLDC):​c.52G>T​(p.Gly18Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00917 in 1,259,152 control chromosomes in the GnomAD database, including 78 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. G18G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0066 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0095 (76 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:9
• Conservation: PhyloP100: 0.822
• 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

LINC02851 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0070572793).
• BP6: Variant 9-6645448-C-A is Benign according to our data. Variant chr9-6645448-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 367208.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00658 (1000/151886) while in subpopulation NFE AF = 0.00938 (637/67934). AF 95% confidence interval is 0.00877. There are 2 homozygotes in GnomAd4. There are 517 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 2 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.52G>T	p.Gly18Cys	missense	Exon 1 of 25	NP_000161.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	ENST00000321612.8	TSL:1 MANE Select	c.52G>T	p.Gly18Cys	missense	Exon 1 of 25	ENSP00000370737.4
	GLDC	ENST00000920236.1		c.52G>T	p.Gly18Cys	missense	Exon 1 of 25	ENSP00000590295.1
	GLDC	ENST00000953081.1		c.52G>T	p.Gly18Cys	missense	Exon 1 of 26	ENSP00000623139.1

Frequencies

GnomAD3 genomes AF: 0.00659 AC: 1000 AN: 151778 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00174

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00551

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.00372

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0255

Gnomad NFE AF: 0.00938

Gnomad OTH AF: 0.00576

GnomAD2 exomes AF: 0.0155 AC: 72 AN: 4648 AF XY: 0.0152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0302

Gnomad NFE exome AF: 0.0154

Gnomad OTH exome AF: 0.00926

GnomAD4 exome AF: 0.00952 AC: 10545 AN: 1107266 Hom.: 76 Cov.: 31 AF XY: 0.00945 AC XY: 5027 AN XY: 531864

African (AFR) AF: 0.00156 AC: 35 AN: 22414

American (AMR) AF: 0.00320 AC: 26 AN: 8114

Ashkenazi Jewish (ASJ) AF: 0.000874 AC: 12 AN: 13726

East Asian (EAS) AF: 0.00 AC: 0 AN: 25090

South Asian (SAS) AF: 0.00364 AC: 93 AN: 25570

European-Finnish (FIN) AF: 0.0222 AC: 531 AN: 23926

Middle Eastern (MID) AF: 0.00928 AC: 27 AN: 2910

European-Non Finnish (NFE) AF: 0.0101 AC: 9515 AN: 941282

Other (OTH) AF: 0.00692 AC: 306 AN: 44234

GnomAD4 genome AF: 0.00658 AC: 1000 AN: 151886 Hom.: 2 Cov.: 32 AF XY: 0.00696 AC XY: 517 AN XY: 74254

African (AFR) AF: 0.00173 AC: 72 AN: 41512

American (AMR) AF: 0.00551 AC: 84 AN: 15254

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5150

South Asian (SAS) AF: 0.00373 AC: 18 AN: 4832

European-Finnish (FIN) AF: 0.0156 AC: 163 AN: 10428

Middle Eastern (MID) AF: 0.0274 AC: 8 AN: 292

European-Non Finnish (NFE) AF: 0.00938 AC: 637 AN: 67934

Other (OTH) AF: 0.00570 AC: 12 AN: 2106

Alfa AF: 0.00309 Hom.: 0

Bravo AF: 0.00531

ExAC AF: 0.00274 AC: 24

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Glycine encephalopathy (4)
-	-	3	not provided (3)
-	-	2	not specified (2)
-	-	1	GLDC-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.030
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.24	T
Eigen	Benign	-0.16
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.42	T
MetaRNN	Benign	0.0071	T
MetaSVM	Pathogenic	0.90	D
MutationAssessor	Benign	0.0	N
PhyloP100		0.82
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	0.010	N
REVEL	Uncertain	0.48
Sift	Benign	0.14	T
Sift4G	Benign	0.17	T
Polyphen		0.97	D
Vest4		0.38
MPC		0.31
ClinPred		0.051	T
GERP RS		3.6
PromoterAI		0.012	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.16
gMVP		0.48
Mutation Taster		=96/4	polymorphism

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: rs535143891; hg19: chr9-6645448; COSMIC: COSV58681545; COSMIC: COSV58681545;