NM_000170.3:c.2113G>A

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM1BP4_StrongBP6BS1BS2

The NM_000170.3(GLDC):c.2113G>A(p.Val705Met) variant causes a missense change. The variant allele was found at a frequency of 0.00281 in 1,611,080 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts 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. V705E) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0036 ( 5 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 25 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:11

Conservation

PhyloP100: 5.81

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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

PM1

In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000170.3

BP4

Computational evidence support a benign effect (MetaRNN=0.015131503).

BP6

Variant 9-6556242-C-T is Benign according to our data. Variant chr9-6556242-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 462865.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00364 (554/152296) while in subpopulation AMR AF = 0.00733 (112/15286). AF 95% confidence interval is 0.00623. There are 5 homozygotes in GnomAd4. There are 303 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 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.2113G>A	p.Val705Met	missense	Exon 18 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.2113G>A	p.Val705Met	missense	Exon 18 of 25	ENSP00000370737.4	P23378
GLDC	ENST00000638233.1	TSL:1	n.548G>A		non_coding_transcript_exon	Exon 4 of 11
GLDC	ENST00000639443.1	TSL:1	n.1681G>A		non_coding_transcript_exon	Exon 14 of 21

Frequencies

GnomAD3 genomes

AF:

0.00365

AC:

555

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00734

Gnomad ASJ

AF:

0.0121

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00352

Gnomad FIN

AF:

0.0120

Gnomad MID

AF:

0.0380

Gnomad NFE

AF:

0.00315

Gnomad OTH

AF:

0.00573

GnomAD2 exomes

AF:

0.00370

AC:

930

AN:

251452

AF XY:

0.00376

show subpopulations

Gnomad AFR exome

AF:

0.000492

Gnomad AMR exome

AF:

0.00269

Gnomad ASJ exome

AF:

0.00952

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.00336

Gnomad OTH exome

AF:

0.00684

GnomAD4 exome

AF:

0.00273

AC:

3978

AN:

1458784

Hom.:

Cov.:

AF XY:

0.00285

AC XY:

2072

AN XY:

725906

show subpopulations

African (AFR)

AF:

0.00132

AC:

AN:

33418

American (AMR)

AF:

0.00288

AC:

129

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.0103

AC:

269

AN:

26120

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39680

South Asian (SAS)

AF:

0.00325

AC:

280

AN:

86202

European-Finnish (FIN)

AF:

0.0109

AC:

580

AN:

53420

Middle Eastern (MID)

AF:

0.0319

AC:

184

AN:

5760

European-Non Finnish (NFE)

AF:

0.00201

AC:

2232

AN:

1109168

Other (OTH)

AF:

0.00430

AC:

259

AN:

60294

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.467

Heterozygous variant carriers

210

421

631

842

1052

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

140

210

280

350

<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:

0.00364

AC:

554

AN:

152296

Hom.:

Cov.:

AF XY:

0.00407

AC XY:

303

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.000457

AC:

AN:

41568

American (AMR)

AF:

0.00733

AC:

112

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.0121

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00353

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.0120

AC:

127

AN:

10618

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00315

AC:

214

AN:

68024

Other (OTH)

AF:

0.00567

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

104

130

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00106

Hom.:

Bravo

AF:

0.00331

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00326

AC:

ExAC

AF:

0.00365

AC:

443

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00469

EpiControl

AF:

0.00480

ClinVar

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (6)

Glycine encephalopathy (3)

not provided (2)

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.44

BayesDel_addAF

Benign

-0.0098

BayesDel_noAF

Pathogenic

0.21

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.78

Eigen

Uncertain

0.54

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.98

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.69

MutationAssessor

Pathogenic

2.9

PhyloP100

5.8

PrimateAI

Uncertain

0.69

PROVEAN

Uncertain

-2.4

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0080

Polyphen

0.95

Vest4

0.90

MVP

0.98

MPC

0.25

ClinPred

0.021

GERP RS

4.5

Varity_R

0.45

gMVP

0.88

Mutation Taster

=83/17

polymorphism

(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