9-6589230-C-T

Position:

chr9-6589230-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_000170.3(GLDC):c.1545G>A(p.Arg515Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.026 in 1,609,682 control chromosomes in the GnomAD database, including 660 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.021 ( 54 hom., cov: 32)

Exomes 𝑓: 0.027 ( 606 hom. )

Consequence

GLDC
NM_000170.3 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts U:1B:8

Conservation

PhyloP100: 0.614

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 Benign. Variant got -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.45).

BP6

Variant 9-6589230-C-T is Benign according to our data. Variant chr9-6589230-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 255453.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6589230-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=0.614 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0212 (3228/152150) while in subpopulation NFE AF= 0.0304 (2065/67996). AF 95% confidence interval is 0.0293. There are 54 homozygotes in gnomad4. There are 1535 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 54 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.1545G>A	p.Arg515Arg	synonymous_variant	12/25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GLDC	ENST00000321612.8 link	c.1545G>A	p.Arg515Arg	synonymous_variant	12/25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.0212

AC:

3228

AN:

152032

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00507

Gnomad AMI

AF:

0.0329

Gnomad AMR

AF:

0.0277

Gnomad ASJ

AF:

0.0326

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00518

Gnomad FIN

AF:

0.0277

Gnomad MID

AF:

0.0506

Gnomad NFE

AF:

0.0304

Gnomad OTH

AF:

0.0263

GnomAD3 exomes

AF:

0.0227

AC:

5701

AN:

251474

Hom.:

AF XY:

0.0230

AC XY:

3128

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00511

Gnomad AMR exome

AF:

0.0215

Gnomad ASJ exome

AF:

0.0335

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00568

Gnomad FIN exome

AF:

0.0281

Gnomad NFE exome

AF:

0.0313

Gnomad OTH exome

AF:

0.0319

GnomAD4 exome

AF:

0.0265

AC:

38649

AN:

1457532

Hom.:

606

Cov.:

AF XY:

0.0262

AC XY:

18983

AN XY:

725458

show subpopulations

Gnomad4 AFR exome

AF:

0.00416

Gnomad4 AMR exome

AF:

0.0229

Gnomad4 ASJ exome

AF:

0.0325

Gnomad4 EAS exome

AF:

0.0000504

Gnomad4 SAS exome

AF:

0.00611

Gnomad4 FIN exome

AF:

0.0274

Gnomad4 NFE exome

AF:

0.0297

Gnomad4 OTH exome

AF:

0.0261

GnomAD4 genome

AF:

0.0212

AC:

3228

AN:

152150

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1535

AN XY:

74396

show subpopulations

Gnomad4 AFR

AF:

0.00506

Gnomad4 AMR

AF:

0.0276

Gnomad4 ASJ

AF:

0.0326

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00519

Gnomad4 FIN

AF:

0.0277

Gnomad4 NFE

AF:

0.0304

Gnomad4 OTH

AF:

0.0260

Alfa

AF:

0.0211

Hom.:

Bravo

AF:

0.0217

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0332

EpiControl

AF:

0.0394

ClinVar

Significance: Benign/Likely benign

Submissions summary: Uncertain:1Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Uncertain:1Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Uncertain significance, no assertion criteria provided	curation	SingHealth Duke-NUS Institute of Precision Medicine	Jun 07, 2017	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jun 28, 2017	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 27, 2018	Variant summary: GLDC c.1545G>A alters a non-conserved nucleotide resulting in a synonymous change. The variant allele was found at a frequency of 0.022 in 277184 control chromosomes in the gnomAD database, including 99 homozygotes. The observed variant frequency is approximately 7-fold above the estimated maximal expected allele frequency for a pathogenic variant in GLDC causing Glycine Encephalopathy (Non-Ketotic Hyperglycinemia) phenotype (0.0031), strongly suggesting that the variant is benign. c.1545G>A has been reported in the literature in an individual affected with Glycine Encephalopathy (Non-Ketotic Hyperglycinemia), though this patient had two pathogenic mutations in trans, supporting a benign impact of the variant. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and both classified the variant as benign. Based on the evidence outlined above, the variant was classified as benign. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 12, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.9

DANN

Benign

0.42

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

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

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over