rs8052579

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.62C>T(p.Ser21Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.797 in 149,294 control chromosomes in the GnomAD database, including 48,741 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.80 ( 48741 hom., cov: 34)

Exomes 𝑓: 0.64 ( 156214 hom. )

Failed GnomAD Quality Control

Consequence

GCSH
NM_004483.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.564

Publications

22 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=1.391188E-6).

BP6

Variant 16-81096217-G-A is Benign according to our data. Variant chr16-81096217-G-A is described in ClinVar as Benign. ClinVar VariationId is 1164317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.905 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCSH	NM_004483.5 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2
GCSH	XM_017023136.3 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 5		XP_016878625.1
GCSH	NR_033249.2 link	n.179C>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
GCSH	ENST00000315467.9 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 6	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 6	5		ENSP00000491651.1

Frequencies

GnomAD3 genomes

AF:

0.797

AC:

118919

AN:

149186

Hom.:

48732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.577

Gnomad AMI

AF:

0.990

Gnomad AMR

AF:

0.844

Gnomad ASJ

AF:

0.919

Gnomad EAS

AF:

0.725

Gnomad SAS

AF:

0.827

Gnomad FIN

AF:

0.821

Gnomad MID

AF:

0.910

Gnomad NFE

AF:

0.911

Gnomad OTH

AF:

0.834

GnomAD2 exomes

AF:

0.540

AC:

696

AN:

1288

AF XY:

0.552

show subpopulations

Gnomad AFR exome

AF:

0.500

Gnomad AMR exome

AF:

0.540

Gnomad ASJ exome

AF:

0.525

Gnomad EAS exome

AF:

0.464

Gnomad FIN exome

AF:

0.500

Gnomad NFE exome

AF:

0.552

Gnomad OTH exome

AF:

0.595

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

0.642

AC:

671291

AN:

1045944

Hom.:

156214

Cov.:

AF XY:

0.647

AC XY:

327531

AN XY:

506550

show subpopulations

African (AFR)

AF:

0.481

AC:

10807

AN:

22460

American (AMR)

AF:

0.789

AC:

6964

AN:

8822

Ashkenazi Jewish (ASJ)

AF:

0.795

AC:

11604

AN:

14596

East Asian (EAS)

AF:

0.703

AC:

18620

AN:

26496

South Asian (SAS)

AF:

0.603

AC:

21148

AN:

35068

European-Finnish (FIN)

AF:

0.803

AC:

20541

AN:

25570

Middle Eastern (MID)

AF:

0.715

AC:

2083

AN:

2914

European-Non Finnish (NFE)

AF:

0.635

AC:

550311

AN:

866954

Other (OTH)

AF:

0.678

AC:

29213

AN:

43064

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.701

Heterozygous variant carriers

19517

39034

58550

78067

97584

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

18064

36128

54192

72256

90320

<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:

0.797

AC:

118945

AN:

149294

Hom.:

48741

Cov.:

AF XY:

0.793

AC XY:

57799

AN XY:

72908

show subpopulations

African (AFR)

AF:

0.576

AC:

23687

AN:

41114

American (AMR)

AF:

0.844

AC:

12662

AN:

14998

Ashkenazi Jewish (ASJ)

AF:

0.919

AC:

3141

AN:

3418

East Asian (EAS)

AF:

0.726

AC:

3673

AN:

5056

South Asian (SAS)

AF:

0.828

AC:

3913

AN:

4726

European-Finnish (FIN)

AF:

0.821

AC:

8458

AN:

10308

Middle Eastern (MID)

AF:

0.907

AC:

263

AN:

290

European-Non Finnish (NFE)

AF:

0.911

AC:

60563

AN:

66448

Other (OTH)

AF:

0.833

AC:

1706

AN:

2048

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1081

2161

3242

4322

5403

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

842

1684

2526

3368

4210

<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:

0.797

Hom.:

5187

ExAC

AF:

0.296

AC:

2237

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Aug 10, 2021

Genome-Nilou Lab

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

GCSH-related disorder

Benign:1

Nov 25, 2020

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.63

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0

.;.;.;T;.;.;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.044

LIST_S2

Benign

0.25

T;T;T;T;T;T;T

MetaRNN

Benign

0.0000014

T;T;T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.0

.;.;.;N;.;.;.

PhyloP100

0.56

PrimateAI

Uncertain

0.75

PROVEAN

Benign

0.0

.;.;.;N;.;.;.

REVEL

Benign

0.0

Sift

Pathogenic

0.0

.;.;.;T;.;.;.

Sift4G

Pathogenic

0.0

.;.;.;T;.;.;.

Vest4

0.0

ClinPred

0.0071

GERP RS

0.18

PromoterAI

-0.14

Neutral

(source)

Varity_R

0.039

gMVP

0.33

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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