9-6589230-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -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 (★★). Synonymous variant affecting the same amino acid position (i.e. R515R) has been classified 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

Publications

17 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=-0.45).

BP6

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

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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 54 AR,Unknown gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000170.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GLDC	NM_000170.3	MANE Select	c.1545G>A	p.Arg515Arg	synonymous	Exon 12 of 25	NP_000161.2	P23378

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GLDC	ENST00000321612.8	TSL:1 MANE Select	c.1545G>A	p.Arg515Arg	synonymous	Exon 12 of 25	ENSP00000370737.4	P23378
GLDC	ENST00000639443.1	TSL:1	n.1113G>A		non_coding_transcript_exon	Exon 8 of 21
GLDC	ENST00000920236.1		c.1545G>A	p.Arg515Arg	synonymous	Exon 12 of 25	ENSP00000590295.1

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

GnomAD2 exomes

AF:

0.0227

AC:

5701

AN:

251474

AF XY:

0.0230

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 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

African (AFR)

AF:

0.00416

AC:

139

AN:

33418

American (AMR)

AF:

0.0229

AC:

1026

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.0325

AC:

848

AN:

26104

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39672

South Asian (SAS)

AF:

0.00611

AC:

527

AN:

86184

European-Finnish (FIN)

AF:

0.0274

AC:

1461

AN:

53396

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5762

European-Non Finnish (NFE)

AF:

0.0297

AC:

32943

AN:

1108068

Other (OTH)

AF:

0.0261

AC:

1571

AN:

60208

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.468

Heterozygous variant carriers

1674

3348

5023

6697

8371

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1160

2320

3480

4640

5800

<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:

0.0212

AC:

3228

AN:

152150

Hom.:

Cov.:

AF XY:

0.0206

AC XY:

1535

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00506

AC:

210

AN:

41518

American (AMR)

AF:

0.0276

AC:

422

AN:

15282

Ashkenazi Jewish (ASJ)

AF:

0.0326

AC:

113

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5164

South Asian (SAS)

AF:

0.00519

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.0277

AC:

293

AN:

10582

Middle Eastern (MID)

AF:

0.0510

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0304

AC:

2065

AN:

67996

Other (OTH)

AF:

0.0260

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

159

318

477

636

795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

144

180

<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:

0.0211

Hom.:

Bravo

AF:

0.0217

Asia WGS

AF:

0.00202

AC:

AN:

3478

EpiCase

AF:

0.0332

EpiControl

AF:

0.0394

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycine encephalopathy (4)

not specified (3)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.45

CADD

Benign

6.9

(source)

DANN

Benign

0.42

PhyloP100

0.61

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over