NM_004483.5:c.261C>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_004483.5(GCSH):c.261C>G(p.Leu87Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00822 in 1,611,310 control chromosomes in the GnomAD database, including 564 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.037 ( 286 hom., cov: 32)

Exomes 𝑓: 0.0052 ( 278 hom. )

Consequence

GCSH
NM_004483.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.285

Publications

4 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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.52).

BP6

Variant 16-81087632-G-C is Benign according to our data. Variant chr16-81087632-G-C is described in ClinVar as Benign. ClinVar VariationId is 462903.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.285 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004483.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	NM_004483.5	MANE Select	c.261C>G	p.Leu87Leu	synonymous	Exon 3 of 5	NP_004474.2
	GCSH	NR_033249.2		n.345+2969C>G		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GCSH	ENST00000315467.9	TSL:1 MANE Select	c.261C>G	p.Leu87Leu	synonymous	Exon 3 of 5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1	TSL:5	c.261C>G	p.Leu87Leu	synonymous	Exon 3 of 6	ENSP00000492798.1
ENSG00000260643	ENST00000564536.2	TSL:5	c.261C>G	p.Leu87Leu	synonymous	Exon 3 of 6	ENSP00000491651.1

Frequencies

GnomAD3 genomes

AF:

0.0370

AC:

5625

AN:

152046

Hom.:

285

Cov.:

show subpopulations

Gnomad AFR

AF:

0.122

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0132

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.0137

Gnomad SAS

AF:

0.00476

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0253

Gnomad NFE

AF:

0.00144

Gnomad OTH

AF:

0.0291

GnomAD2 exomes

AF:

0.0122

AC:

3056

AN:

251220

AF XY:

0.00989

show subpopulations

Gnomad AFR exome

AF:

0.122

Gnomad AMR exome

AF:

0.00700

Gnomad ASJ exome

AF:

0.0332

Gnomad EAS exome

AF:

0.00946

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.00175

Gnomad OTH exome

AF:

0.00897

GnomAD4 exome

AF:

0.00521

AC:

7598

AN:

1459146

Hom.:

278

Cov.:

AF XY:

0.00488

AC XY:

3545

AN XY:

726108

show subpopulations

African (AFR)

AF:

0.116

AC:

3809

AN:

32752

American (AMR)

AF:

0.00821

AC:

367

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.0315

AC:

821

AN:

26056

East Asian (EAS)

AF:

0.0156

AC:

620

AN:

39670

South Asian (SAS)

AF:

0.00238

AC:

205

AN:

86212

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

53340

Middle Eastern (MID)

AF:

0.0211

AC:

121

AN:

5726

European-Non Finnish (NFE)

AF:

0.000820

AC:

911

AN:

1110456

Other (OTH)

AF:

0.0123

AC:

738

AN:

60218

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.414

Heterozygous variant carriers

359

718

1076

1435

1794

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

142

284

426

568

710

<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:

0.0371

AC:

5643

AN:

152164

Hom.:

286

Cov.:

AF XY:

0.0359

AC XY:

2672

AN XY:

74402

show subpopulations

African (AFR)

AF:

0.122

AC:

5061

AN:

41492

American (AMR)

AF:

0.0132

AC:

201

AN:

15268

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3468

East Asian (EAS)

AF:

0.0139

AC:

AN:

5178

South Asian (SAS)

AF:

0.00435

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.0306

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00144

AC:

AN:

68018

Other (OTH)

AF:

0.0288

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

258

517

775

1034

1292

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

180

240

300

<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:

0.0168

Hom.:

Bravo

AF:

0.0433

Asia WGS

AF:

0.0160

AC:

AN:

3478

EpiCase

AF:

0.00316

EpiControl

AF:

0.00279

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

May 04, 2021

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

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 v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.52

CADD

Benign

3.0

(source)

DANN

Benign

0.63

PhyloP100

0.28

Mutation Taster

=93/7

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over