chr9-6645310-C-A

Position:

• chr9-6645310-C-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 4P and 5B. PM1 PM2 BP4_Strong BP6

The NM_000170.3(GLDC):​c.190G>T​(p.Ala64Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000266 in 1,594,386 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A64T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00026 (1 hom.)
• Consequence: GLDC NM_000170.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 0.758

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]

ACMG classification

Verdict is Likely_benign. Variant got -1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 9 uncertain in NM_000170.3
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.017509818).
• BP6: Variant 9-6645310-C-A is Benign according to our data. Variant chr9-6645310-C-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462861.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Uncertain_significance=1}. Variant chr9-6645310-C-A is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GLDC	NM_000170.3	c.190G>T	p.Ala64Ser	missense_variant	1/25	ENST00000321612.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GLDC	ENST00000321612.8	c.190G>T	p.Ala64Ser	missense_variant	1/25	1	NM_000170.3	P1

Frequencies

GnomAD3 genomes AF: 0.000355 AC: 54 AN: 152124 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000850

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000279

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000412 AC: 88 AN: 213782 Hom.: 0 AF XY: 0.000412 AC XY: 48 AN XY: 116528

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000674

Gnomad ASJ exome AF: 0.00361

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000296

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000232

Gnomad OTH exome AF: 0.000760

GnomAD4 exome AF: 0.000257 AC: 370 AN: 1442144 Hom.: 1 Cov.: 32 AF XY: 0.000275 AC XY: 197 AN XY: 716382

Gnomad4 AFR exome AF: 0.000156

Gnomad4 AMR exome AF: 0.000678

Gnomad4 ASJ exome AF: 0.00388

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000300

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000141

Gnomad4 OTH exome AF: 0.000723

GnomAD4 genome AF: 0.000355 AC: 54 AN: 152242 Hom.: 0 Cov.: 33 AF XY: 0.000255 AC XY: 19 AN XY: 74446

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.000849

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000651 Hom.: 0

Bravo AF: 0.000400

ExAC AF: 0.000224 AC: 27

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Inborn genetic diseases Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2021

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 21, 2020

- -

GLDC-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 21, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.94
DEOGEN2	Benign	0.29	T
Eigen	Benign	-0.47
Eigen_PC	Benign	-0.27
FATHMM_MKL	Benign	0.58	D
LIST_S2	Uncertain	0.89	D
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.018	T
MetaSVM	Uncertain	0.44	D
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.97	N
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	-0.87	N
REVEL	Uncertain	0.32
Sift	Benign	0.55	T
Sift4G	Benign	0.55	T
Polyphen		0.0010	B
Vest4		0.10
MutPred		0.24		Gain of phosphorylation at A64 (P = 0.0201);
MVP		0.92
MPC		0.044
ClinPred		0.020	T
GERP RS		2.8
Varity_R		0.20
gMVP		0.50

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

Publications

LitVar

Other links and lift over

dbSNP: rs141601131; hg19: chr9-6645310;