rs35374927

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.501G>A(p.Glu167Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.267 in 1,612,998 control chromosomes in the GnomAD database, including 59,408 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.23 ( 4243 hom., cov: 32)

Exomes 𝑓: 0.27 ( 55165 hom. )

Consequence

GLDC
NM_000170.3 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.417

Publications

13 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:

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=-0.35).

BP6

Variant 9-6610326-C-T is Benign according to our data. Variant chr9-6610326-C-T is described in ClinVar as Benign. ClinVar VariationId is 255459.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.417 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GLDC	NM_000170.3 link	c.501G>A	p.Glu167Glu	synonymous_variant	Exon 4 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.501G>A	p.Glu167Glu	synonymous_variant	Exon 4 of 25	1	NM_000170.3	ENSP00000370737.4		P23378

Frequencies

GnomAD3 genomes

AF:

0.226

AC:

34405

AN:

152020

Hom.:

4241

Cov.:

show subpopulations

Gnomad AFR

AF:

0.144

Gnomad AMI

AF:

0.0965

Gnomad AMR

AF:

0.219

Gnomad ASJ

AF:

0.221

Gnomad EAS

AF:

0.0919

Gnomad SAS

AF:

0.270

Gnomad FIN

AF:

0.261

Gnomad MID

AF:

0.264

Gnomad NFE

AF:

0.281

Gnomad OTH

AF:

0.245

GnomAD2 exomes

AF:

0.238

AC:

59621

AN:

250824

AF XY:

0.245

show subpopulations

Gnomad AFR exome

AF:

0.143

Gnomad AMR exome

AF:

0.167

Gnomad ASJ exome

AF:

0.225

Gnomad EAS exome

AF:

0.0887

Gnomad FIN exome

AF:

0.256

Gnomad NFE exome

AF:

0.286

Gnomad OTH exome

AF:

0.247

GnomAD4 exome

AF:

0.271

AC:

395632

AN:

1460858

Hom.:

55165

Cov.:

AF XY:

0.272

AC XY:

197641

AN XY:

726746

show subpopulations

African (AFR)

AF:

0.143

AC:

4791

AN:

33476

American (AMR)

AF:

0.176

AC:

7876

AN:

44696

Ashkenazi Jewish (ASJ)

AF:

0.227

AC:

5919

AN:

26130

East Asian (EAS)

AF:

0.0829

AC:

3290

AN:

39700

South Asian (SAS)

AF:

0.274

AC:

23590

AN:

86190

European-Finnish (FIN)

AF:

0.265

AC:

14149

AN:

53408

Middle Eastern (MID)

AF:

0.292

AC:

1683

AN:

5768

European-Non Finnish (NFE)

AF:

0.287

AC:

319121

AN:

1111116

Other (OTH)

AF:

0.252

AC:

15213

AN:

60374

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

15352

30704

46056

61408

76760

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10398

20796

31194

41592

51990

<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:

0.226

AC:

34418

AN:

152140

Hom.:

4243

Cov.:

AF XY:

0.226

AC XY:

16781

AN XY:

74380

show subpopulations

African (AFR)

AF:

0.144

AC:

5991

AN:

41544

American (AMR)

AF:

0.219

AC:

3341

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.221

AC:

768

AN:

3470

East Asian (EAS)

AF:

0.0921

AC:

477

AN:

5180

South Asian (SAS)

AF:

0.270

AC:

1305

AN:

4826

European-Finnish (FIN)

AF:

0.261

AC:

2759

AN:

10574

Middle Eastern (MID)

AF:

0.260

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.281

AC:

19092

AN:

67948

Other (OTH)

AF:

0.247

AC:

521

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

1358

2716

4073

5431

6789

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

378

756

1134

1512

1890

<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:

0.253

Hom.:

2368

Bravo

AF:

0.216

Asia WGS

AF:

0.186

AC:

647

AN:

3478

EpiCase

AF:

0.287

EpiControl

AF:

0.284

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:5

Sep 16, 2020

Natera, Inc.

Significance:Benign

Review Status:no assertion criteria provided

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. -

Sep 11, 2021

Fulgent Genetics, Fulgent Genetics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:3

Apr 20, 2017

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jul 15, 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

-0.35

CADD

Benign

5.7

(source)

DANN

Benign

0.46

PhyloP100

0.42

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