9-6588403-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 4P and 20B. PS3BP4_StrongBP6_Very_StrongBS1BS2

The NM_000170.3(GLDC):c.1705G>A(p.Ala569Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00492 in 1,609,056 control chromosomes in the GnomAD database, including 42 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). ClinVar reports functional evidence for this variant: "SCV000538035: Multiple in vitro functional assays have demonstrated this variant results in reduced or undetectable GLDC activity (Narisawa et al., 2012" and additional evidence is available in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A569P) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0040 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0050 ( 41 hom. )

Consequence

GLDC
NM_000170.3 missense, splice_region

Scores

Splicing: ADA: 0.00002804

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1U:1B:11

Conservation

PhyloP100: 0.438

Publications

9 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 -16 ACMG points.

PS3

PS3 evidence extracted from ClinVar submissions: SCV000538035: Multiple in vitro functional assays have demonstrated this variant results in reduced or undetectable GLDC activity (Narisawa et al., 2012; Swanson et 2015).

BP4

Computational evidence support a benign effect (MetaRNN=0.014870584).

BP6

Variant 9-6588403-C-T is Benign according to our data. Variant chr9-6588403-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00396 (603/152200) while in subpopulation NFE AF = 0.00478 (325/68002). AF 95% confidence interval is 0.00435. There are 1 homozygotes in GnomAd4. There are 327 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 41 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.1705G>A	p.Ala569Thr	missense splice_region	Exon 14 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.1705G>A	p.Ala569Thr	missense splice_region	Exon 14 of 25	ENSP00000370737.4	P23378
GLDC	ENST00000639443.1	TSL:1	n.1273G>A		splice_region non_coding_transcript_exon	Exon 10 of 21
GLDC	ENST00000920236.1		c.1705G>A	p.Ala569Thr	missense splice_region	Exon 14 of 25	ENSP00000590295.1

Frequencies

GnomAD3 genomes

AF:

0.00396

AC:

603

AN:

152082

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00113

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0176

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00478

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00430

AC:

1081

AN:

251442

AF XY:

0.00407

show subpopulations

Gnomad AFR exome

AF:

0.000615

Gnomad AMR exome

AF:

0.00153

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0187

Gnomad NFE exome

AF:

0.00514

Gnomad OTH exome

AF:

0.00489

GnomAD4 exome

AF:

0.00502

AC:

7318

AN:

1456856

Hom.:

Cov.:

AF XY:

0.00478

AC XY:

3469

AN XY:

725202

show subpopulations

African (AFR)

AF:

0.000719

AC:

AN:

33372

American (AMR)

AF:

0.00141

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26102

East Asian (EAS)

AF:

0.00

AC:

AN:

39684

South Asian (SAS)

AF:

0.00

AC:

AN:

86170

European-Finnish (FIN)

AF:

0.0198

AC:

1055

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5754

European-Non Finnish (NFE)

AF:

0.00537

AC:

5947

AN:

1107444

Other (OTH)

AF:

0.00380

AC:

229

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

313

627

940

1254

1567

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

218

436

654

872

1090

<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:

0.00396

AC:

603

AN:

152200

Hom.:

Cov.:

AF XY:

0.00439

AC XY:

327

AN XY:

74408

show subpopulations

African (AFR)

AF:

0.00113

AC:

AN:

41536

American (AMR)

AF:

0.00255

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.0176

AC:

186

AN:

10592

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00478

AC:

325

AN:

68002

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

127

159

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

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:

0.00364

Hom.:

Bravo

AF:

0.00274

TwinsUK

AF:

0.00863

AC:

ALSPAC

AF:

0.00441

AC:

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.00558

AC:

ExAC

AF:

0.00390

AC:

474

EpiCase

AF:

0.00425

EpiControl

AF:

0.00445

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

Glycine encephalopathy (6)

not provided (6)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.067

BayesDel_addAF

Benign

-0.14

BayesDel_noAF

Uncertain

0.030

CADD

Benign

8.7

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.25

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.40

LIST_S2

Uncertain

0.86

MetaRNN

Benign

0.015

MetaSVM

Uncertain

0.011

MutationAssessor

Benign

0.64

PhyloP100

0.44

PrimateAI

Benign

0.29

PROVEAN

Benign

-0.36

REVEL

Uncertain

0.58

Sift

Benign

0.085

Sift4G

Benign

0.083

Polyphen

0.0

Vest4

0.21

MVP

0.90

MPC

0.045

ClinPred

0.017

GERP RS

-4.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.099

gMVP

0.61

Mutation Taster

=80/20

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000028

dbscSNV1_RF

Benign

0.016

Splicevardb

2.0

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