rs781682244

Positions:

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PM2

The NM_000170.3(GLDC):ā€‹c.2458A>Gā€‹(p.Met820Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,444,454 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (ā˜…).

Frequency

Genomes: not found (cov: 32)
Exomes š‘“: 0.0000028 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense, splice_region

Scores

5
13
1
Splicing: ADA: 0.3357
2

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.48
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1
In a helix (size 33) in uniprot entity GCSP_HUMAN there are 12 pathogenic changes around while only 0 benign (100%) in NM_000170.3
PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
GLDCNM_000170.3 linkuse as main transcriptc.2458A>G p.Met820Val missense_variant, splice_region_variant 21/25 ENST00000321612.8 NP_000161.2 P23378

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
GLDCENST00000321612.8 linkuse as main transcriptc.2458A>G p.Met820Val missense_variant, splice_region_variant 21/251 NM_000170.3 ENSP00000370737.4 P23378

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251440
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135888
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.0000544
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000277
AC:
4
AN:
1444454
Hom.:
0
Cov.:
27
AF XY:
0.00000278
AC XY:
2
AN XY:
719856
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.0000252
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000274
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Glycine encephalopathy Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingCounsylApr 25, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.49
BayesDel_addAF
Uncertain
0.094
D
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.76
D;.;.;.
Eigen
Uncertain
0.35
Eigen_PC
Uncertain
0.40
FATHMM_MKL
Pathogenic
0.97
D
LIST_S2
Pathogenic
0.99
D;D;D;D
M_CAP
Uncertain
0.27
D
MetaRNN
Uncertain
0.68
D;D;D;D
MetaSVM
Uncertain
0.40
D
MutationAssessor
Pathogenic
3.4
M;.;.;.
PrimateAI
Uncertain
0.64
T
PROVEAN
Uncertain
-3.2
D;.;.;.
REVEL
Pathogenic
0.76
Sift
Uncertain
0.0010
D;.;.;.
Sift4G
Pathogenic
0.0010
D;.;.;.
Polyphen
0.28
B;.;.;.
Vest4
0.72
MutPred
0.46
Loss of disorder (P = 0.0987);.;.;.;
MVP
0.89
MPC
0.056
ClinPred
0.87
D
GERP RS
4.7
Varity_R
0.83
gMVP
0.94

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.34
dbscSNV1_RF
Benign
0.60
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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs781682244; hg19: chr9-6550914; API