rs182760732

Variant names:

• chr9-6645460-G-A
• rs182760732
• NM_000170.3:c.40C>T

Your query was ambiguous. Multiple possible variants found:

• chr9-6645460-G-A
• chr9-6645460-G-C
• chr9-6645460-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_000170.3(GLDC):​c.40C>T​(p.Arg14Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000664 in 150,496 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.00300
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.1969403).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3	c.40C>T	p.Arg14Cys	missense_variant	Exon 1 of 25	ENST00000321612.8	NP_000161.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8	c.40C>T	p.Arg14Cys	missense_variant	Exon 1 of 25	1	NM_000170.3	ENSP00000370737.4
LINC02851	ENST00000813373.1	n.124+534G>A		intron_variant	Intron 1 of 2
LINC02851	ENST00000813380.1	n.405+534G>A		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes AF: 0.00000664 AC: 1 AN: 150496 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: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1097328 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 526686

African (AFR) AF: 0.00 AC: 0 AN: 22098

American (AMR) AF: 0.00 AC: 0 AN: 7884

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 13416

East Asian (EAS) AF: 0.00 AC: 0 AN: 24328

South Asian (SAS) AF: 0.00 AC: 0 AN: 25022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23056

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 2860

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 935094

Other (OTH) AF: 0.00 AC: 0 AN: 43570

GnomAD4 genome AF: 0.00000664 AC: 1 AN: 150496 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 73488

African (AFR) AF: 0.00 AC: 0 AN: 40956

American (AMR) AF: 0.00 AC: 0 AN: 15138

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3450

East Asian (EAS) AF: 0.00 AC: 0 AN: 4994

South Asian (SAS) AF: 0.00 AC: 0 AN: 4772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10342

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 298

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67586

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.19
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.97
FATHMM_MKL	Benign	0.032	N
LIST_S2	Benign	0.56	T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.20	T
MetaSVM	Uncertain	0.33	D
MutationAssessor	Benign	0.0	N
PhyloP100		-0.0030
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-0.45	N
REVEL	Benign	0.27
Sift	Benign	0.076	T
Sift4G	Uncertain	0.053	T
Polyphen		0.0	B
Vest4		0.097
MutPred		0.37		Loss of methylation at R14 (P = 0.0065);
MVP		0.78
MPC		0.058
ClinPred		0.66	D
GERP RS		-0.066
PromoterAI		-0.077	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.059
gMVP		0.45
Mutation Taster		=94/6	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: rs182760732; hg19: chr9-6645460;