9-6645251-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BA1

The NM_000170.3(GLDC):c.249G>A(p.Gly83Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.221 in 1,593,952 control chromosomes in the GnomAD database, including 39,747 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G83G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.22 ( 3757 hom., cov: 32)

Exomes 𝑓: 0.22 ( 35990 hom. )

Consequence

GLDC
NM_000170.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: 0.358

Publications

12 publications found

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 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

GLDC links:

LINC02851 (HGNC:):

LINC02851 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.36).

BP6

Variant 9-6645251-C-T is Benign according to our data. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-6645251-C-T is described in CliVar as Benign. Clinvar id is 255456.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.358 with no splicing effect.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.309 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.249G>A	p.Gly83Gly	synonymous_variant	Exon 1 of 25	ENST00000321612.8	NP_000161.2	P23378

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GLDC	ENST00000321612.8 link	c.249G>A	p.Gly83Gly	synonymous_variant	Exon 1 of 25	1	NM_000170.3	ENSP00000370737.4	P23378
LINC02851	ENST00000813373.1 link	n.124+325C>T		intron_variant	Intron 1 of 2
LINC02851	ENST00000813380.1 link	n.405+325C>T		intron_variant	Intron 1 of 2

Frequencies

GnomAD3 genomes

AF:

0.220

AC:

33449

AN:

152032

Hom.:

3742

Cov.:

show subpopulations

Gnomad AFR

AF:

0.217

Gnomad AMI

AF:

0.235

Gnomad AMR

AF:

0.223

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.196

Gnomad SAS

AF:

0.323

Gnomad FIN

AF:

0.228

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.214

Gnomad OTH

AF:

0.217

GnomAD2 exomes

AF:

0.226

AC:

50758

AN:

224878

AF XY:

0.231

show subpopulations

Gnomad AFR exome

AF:

0.216

Gnomad AMR exome

AF:

0.211

Gnomad ASJ exome

AF:

0.211

Gnomad EAS exome

AF:

0.188

Gnomad FIN exome

AF:

0.226

Gnomad NFE exome

AF:

0.213

Gnomad OTH exome

AF:

0.221

GnomAD4 exome

AF:

0.221

AC:

318485

AN:

1441802

Hom.:

35990

Cov.:

AF XY:

0.224

AC XY:

160289

AN XY:

715962

show subpopulations

African (AFR)

AF:

0.217

AC:

6943

AN:

31998

American (AMR)

AF:

0.217

AC:

9367

AN:

43094

Ashkenazi Jewish (ASJ)

AF:

0.207

AC:

5307

AN:

25576

East Asian (EAS)

AF:

0.192

AC:

7307

AN:

38030

South Asian (SAS)

AF:

0.320

AC:

26910

AN:

84020

European-Finnish (FIN)

AF:

0.233

AC:

12214

AN:

52332

Middle Eastern (MID)

AF:

0.218

AC:

1141

AN:

5244

European-Non Finnish (NFE)

AF:

0.214

AC:

236182

AN:

1102178

Other (OTH)

AF:

0.221

AC:

13114

AN:

59330

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

11647

23294

34942

46589

58236

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

8292

16584

24876

33168

41460

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.220

AC:

33492

AN:

152150

Hom.:

3757

Cov.:

AF XY:

0.222

AC XY:

16544

AN XY:

74390

show subpopulations

African (AFR)

AF:

0.217

AC:

9032

AN:

41536

American (AMR)

AF:

0.223

AC:

3408

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

777

AN:

3470

East Asian (EAS)

AF:

0.196

AC:

1013

AN:

5174

South Asian (SAS)

AF:

0.323

AC:

1556

AN:

4820

European-Finnish (FIN)

AF:

0.228

AC:

2413

AN:

10594

Middle Eastern (MID)

AF:

0.207

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.214

AC:

14548

AN:

67946

Other (OTH)

AF:

0.222

AC:

470

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

1356

2711

4067

5422

6778

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

360

720

1080

1440

1800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.216

Hom.:

2714

Bravo

AF:

0.213

Asia WGS

AF:

0.295

AC:

1025

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:4

Nov 20, 2019

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 17, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.36

CADD

Benign

(source)

DANN

Benign

0.96

PhyloP100

0.36

PromoterAI

0.14

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over