Genetic Variant NM_000170.3:c.2458A>T (chr9-6550914-T-A) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 6P and 1B. PM1PM2PM5BP4

The NM_000170.3(GLDC):c.2458A>T(p.Met820Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000692 in 1,444,454 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. 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. M820V) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

GLDC
NM_000170.3 missense, splice_region

Scores

Splicing: ADA: 0.1435

Clinical Significance

Not reported in ClinVar

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]

GLDC links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 5 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;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-6550914-T-C is described in Lovd as [Pathogenic].

BP4

Computational evidence support a benign effect (MetaRNN=0.39976946).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.2458A>T	p.Met820Leu	missense_variant, splice_region_variant	Exon 21 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.2458A>T	p.Met820Leu	missense_variant, splice_region_variant	Exon 21 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.92e-7

AC:

AN:

1444454

Hom.:

Cov.:

AF XY:

0.00

AC XY:

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:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.12e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.084

BayesDel_noAF

Benign

-0.12

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.39

T;.;.;.

Eigen

Benign

-0.094

Eigen_PC

Benign

0.099

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.97

D;D;D;D

M_CAP

Benign

0.035

MetaRNN

Benign

0.40

T;T;T;T

MetaSVM

Benign

-0.55

MutationAssessor

Benign

0.69

N;.;.;.

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-1.9

N;.;.;.

REVEL

Uncertain

0.38

Sift

Benign

0.26

T;.;.;.

Sift4G

Benign

0.26

T;.;.;.

Polyphen

0.0020

B;.;.;.

Vest4

0.61

MutPred

0.51

Loss of methylation at K824 (P = 0.0677);.;.;.;

MVP

0.81

MPC

0.044

ClinPred

0.87

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.67

gMVP

0.91

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.14

dbscSNV1_RF

Benign

0.44

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over