9-6553445-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBS1BS2

The NM_000170.3(GLDC):c.2380G>A(p.Ala794Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00834 in 1,613,672 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A794G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0071 ( 8 hom., cov: 32)

Exomes 𝑓: 0.0085 ( 56 hom. )

Consequence

GLDC
NM_000170.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.0210

Publications

6 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 -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 12 uncertain in NM_000170.3

BP4

Computational evidence support a benign effect (MetaRNN=0.0045828223).

BP6

Variant 9-6553445-C-T is Benign according to our data. Variant chr9-6553445-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255455.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00711 (1082/152252) while in subpopulation AMR AF = 0.00969 (148/15276). AF 95% confidence interval is 0.00893. There are 8 homozygotes in GnomAd4. There are 525 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 8 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.2380G>A	p.Ala794Thr	missense	Exon 20 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.2380G>A	p.Ala794Thr	missense	Exon 20 of 25	ENSP00000370737.4	P23378
GLDC	ENST00000638233.1	TSL:1	n.815G>A		non_coding_transcript_exon	Exon 6 of 11
GLDC	ENST00000639443.1	TSL:1	n.1948G>A		non_coding_transcript_exon	Exon 16 of 21

Frequencies

GnomAD3 genomes

AF:

0.00713

AC:

1084

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00208

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00970

Gnomad ASJ

AF:

0.000865

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00373

Gnomad FIN

AF:

0.0139

Gnomad MID

AF:

0.00949

Gnomad NFE

AF:

0.00957

Gnomad OTH

AF:

0.0129

GnomAD2 exomes

AF:

0.00693

AC:

1743

AN:

251474

AF XY:

0.00701

show subpopulations

Gnomad AFR exome

AF:

0.00228

Gnomad AMR exome

AF:

0.00685

Gnomad ASJ exome

AF:

0.00198

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0123

Gnomad NFE exome

AF:

0.00904

Gnomad OTH exome

AF:

0.00912

GnomAD4 exome

AF:

0.00847

AC:

12383

AN:

1461420

Hom.:

Cov.:

AF XY:

0.00843

AC XY:

6132

AN XY:

727058

show subpopulations

African (AFR)

AF:

0.00152

AC:

AN:

33476

American (AMR)

AF:

0.00682

AC:

305

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00222

AC:

AN:

26134

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00339

AC:

292

AN:

86250

European-Finnish (FIN)

AF:

0.0122

AC:

651

AN:

53420

Middle Eastern (MID)

AF:

0.00381

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00943

AC:

10482

AN:

1111570

Other (OTH)

AF:

0.00863

AC:

521

AN:

60378

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

605

1210

1816

2421

3026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

390

780

1170

1560

1950

<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:

0.00711

AC:

1082

AN:

152252

Hom.:

Cov.:

AF XY:

0.00705

AC XY:

525

AN XY:

74462

show subpopulations

African (AFR)

AF:

0.00207

AC:

AN:

41562

American (AMR)

AF:

0.00969

AC:

148

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00373

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.0139

AC:

148

AN:

10610

Middle Eastern (MID)

AF:

0.0102

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00954

AC:

649

AN:

68026

Other (OTH)

AF:

0.0128

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

110

164

219

274

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00664

Hom.:

Bravo

AF:

0.00635

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.00986

AC:

ESP6500AA

AF:

0.00318

AC:

ESP6500EA

AF:

0.00977

AC:

ExAC

AF:

0.00687

AC:

834

EpiCase

AF:

0.00905

EpiControl

AF:

0.00842

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (6)

Glycine encephalopathy (4)

not specified (3)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.068

BayesDel_addAF

Benign

-0.45

BayesDel_noAF

Benign

-0.42

CADD

Benign

0.021

(source)

DANN

Benign

0.83

DEOGEN2

Benign

0.24

Eigen

Benign

-1.5

Eigen_PC

Benign

-1.5

FATHMM_MKL

Benign

0.073

LIST_S2

Benign

0.46

MetaRNN

Benign

0.0046

MetaSVM

Uncertain

-0.21

MutationAssessor

Benign

0.64

PhyloP100

0.021

PrimateAI

Benign

0.24

PROVEAN

Benign

-0.73

REVEL

Benign

0.21

Sift

Benign

0.49

Sift4G

Benign

0.24

Polyphen

0.0

Vest4

0.16

MVP

0.79

MPC

0.045

ClinPred

0.00060

GERP RS

0.24

Varity_R

0.036

gMVP

0.67

Mutation Taster

=100/0

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