rs8177877

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_004483.5(GCSH):c.218A>G(p.Asn73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00813 in 1,600,706 control chromosomes in the GnomAD database, including 513 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.035 ( 248 hom., cov: 32)

Exomes 𝑓: 0.0053 ( 265 hom. )

Consequence

GCSH
NM_004483.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 4.12

Publications

9 publications found

Variant links:

Genes affected

GCSH (HGNC:4208): (glycine cleavage system protein H) 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 H protein, which transfers the methylamine group of glycine from the P protein to the T protein. Defects in this gene are a cause of nonketotic hyperglycinemia (NKH). Two transcript variants, one protein-coding and the other probably not protein-coding,have been found for this gene. Also, several transcribed and non-transcribed pseudogenes of this gene exist throughout the genome.[provided by RefSeq, Jan 2010]

GCSH Gene-Disease associations (from GenCC):

glycine encephalopathy
Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics
multiple mitochondrial dysfunctions syndrome 7
Inheritance: AR Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, 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

GCSH links:

ENSG00000284512 (HGNC:):

ENSG00000284512 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003116995).

BP6

Variant 16-81090611-T-C is Benign according to our data. Variant chr16-81090611-T-C is described in ClinVar as Benign. ClinVar VariationId is 462901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5 link	c.218A>G	p.Asn73Ser	missense_variant	Exon 2 of 5	ENST00000315467.9	NP_004474.2	P23434

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCSH	ENST00000315467.9 link	c.218A>G	p.Asn73Ser	missense_variant	Exon 2 of 5	1	NM_004483.5	ENSP00000319531.3	P23434
ENSG00000284512	ENST00000640345.1 link	c.218A>G	p.Asn73Ser	missense_variant	Exon 2 of 6	5		ENSP00000492798.1	A0A1W2PS29
ENSG00000260643	ENST00000564536.2 link	c.218A>G	p.Asn73Ser	missense_variant	Exon 2 of 6	5		ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes

AF:

0.0347

AC:

5280

AN:

152080

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.114

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0127

Gnomad ASJ

AF:

0.0349

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.0268

GnomAD2 exomes

AF:

0.0117

AC:

2947

AN:

251428

AF XY:

0.00951

show subpopulations

Gnomad AFR exome

AF:

0.115

Gnomad AMR exome

AF:

0.00671

Gnomad ASJ exome

AF:

0.0331

Gnomad EAS exome

AF:

0.00946

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00176

Gnomad OTH exome

AF:

0.00880

GnomAD4 exome

AF:

0.00532

AC:

7713

AN:

1448508

Hom.:

265

Cov.:

AF XY:

0.00496

AC XY:

3577

AN XY:

721616

show subpopulations

African (AFR)

AF:

0.114

AC:

3794

AN:

33174

American (AMR)

AF:

0.00796

AC:

356

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0327

AC:

852

AN:

26052

East Asian (EAS)

AF:

0.0158

AC:

628

AN:

39626

South Asian (SAS)

AF:

0.00250

AC:

215

AN:

85962

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53412

Middle Eastern (MID)

AF:

0.0213

AC:

115

AN:

5404

European-Non Finnish (NFE)

AF:

0.000910

AC:

1001

AN:

1100278

Other (OTH)

AF:

0.0125

AC:

746

AN:

59892

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

368

736

1105

1473

1841

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

154

308

462

616

770

<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:

0.0348

AC:

5298

AN:

152198

Hom.:

248

Cov.:

AF XY:

0.0336

AC XY:

2499

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.114

AC:

4726

AN:

41504

American (AMR)

AF:

0.0126

AC:

193

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0349

AC:

121

AN:

3472

East Asian (EAS)

AF:

0.0143

AC:

AN:

5180

South Asian (SAS)

AF:

0.00436

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

68020

Other (OTH)

AF:

0.0265

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

247

494

741

988

1235

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<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:

0.0151

Hom.:

244

Bravo

AF:

0.0408

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.107

AC:

469

ESP6500EA

AF:

0.00372

AC:

ExAC

AF:

0.0137

AC:

1658

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Glycine encephalopathy

Benign:1

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.57

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.29

.;.;.;T;.

Eigen

Benign

-0.059

Eigen_PC

Benign

0.15

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.96

D;D;D;D;D

MetaRNN

Benign

0.0031

T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.88

.;.;.;L;.

PhyloP100

4.1

PrimateAI

Benign

0.40

PROVEAN

Uncertain

-3.1

.;.;.;D;.

REVEL

Benign

0.052

Sift

Benign

0.24

.;.;.;T;.

Sift4G

Benign

0.23

.;.;.;T;.

Polyphen

0.0040

.;.;.;B;.

Vest4

0.082

MPC

0.32

ClinPred

0.034

GERP RS

5.6

PromoterAI

0.020

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.41

gMVP

0.52

Mutation Taster

=97/3

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