rs8177847

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.90C>G(p.Pro30Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00733 in 1,319,306 control chromosomes in the GnomAD database, including 270 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.032 ( 206 hom., cov: 34)

Exomes 𝑓: 0.0041 ( 64 hom. )

Consequence

GCSH
NM_004483.5 synonymous

Scores

Clinical Significance

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

Conservation

PhyloP100: 0.728

Publications

2 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=-0.81).

BP6

Variant 16-81096189-G-C is Benign according to our data. Variant chr16-81096189-G-C is described in ClinVar as Benign. ClinVar VariationId is 462910.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.728 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.101 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5 link	c.90C>G	p.Pro30Pro	synonymous_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2	P23434
GCSH	XM_017023136.3 link	c.90C>G	p.Pro30Pro	synonymous_variant	Exon 1 of 5		XP_016878625.1
GCSH	NR_033249.2 link	n.207C>G		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCSH	ENST00000315467.9 link	c.90C>G	p.Pro30Pro	synonymous_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3	P23434
ENSG00000284512	ENST00000640345.1 link	c.90C>G	p.Pro30Pro	synonymous_variant	Exon 1 of 6	5		ENSP00000492798.1	A0A1W2PS29
ENSG00000260643	ENST00000564536.2 link	c.90C>G	p.Pro30Pro	synonymous_variant	Exon 1 of 6	5		ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes

AF:

0.0317

AC:

4825

AN:

152084

Hom.:

205

Cov.:

show subpopulations

Gnomad AFR

AF:

0.104

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0113

Gnomad ASJ

AF:

0.0346

Gnomad EAS

AF:

0.0141

Gnomad SAS

AF:

0.00434

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0255

Gnomad NFE

AF:

0.00128

Gnomad OTH

AF:

0.0249

GnomAD2 exomes

AF:

0.00286

AC:

AN:

5236

AF XY:

0.00214

show subpopulations

Gnomad AFR exome

AF:

0.0517

Gnomad AMR exome

AF:

0.00225

Gnomad ASJ exome

AF:

0.0113

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00104

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00414

AC:

4829

AN:

1167114

Hom.:

Cov.:

AF XY:

0.00395

AC XY:

2234

AN XY:

565118

show subpopulations

African (AFR)

AF:

0.101

AC:

2371

AN:

23480

American (AMR)

AF:

0.00953

AC:

AN:

9868

Ashkenazi Jewish (ASJ)

AF:

0.0318

AC:

504

AN:

15830

East Asian (EAS)

AF:

0.0177

AC:

478

AN:

27070

South Asian (SAS)

AF:

0.00174

AC:

AN:

41420

European-Finnish (FIN)

AF:

0.000112

AC:

AN:

26844

Middle Eastern (MID)

AF:

0.0157

AC:

AN:

3190

European-Non Finnish (NFE)

AF:

0.000747

AC:

726

AN:

972088

Other (OTH)

AF:

0.0112

AC:

531

AN:

47324

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.440

Heterozygous variant carriers

201

402

604

805

1006

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.0318

AC:

4841

AN:

152192

Hom.:

206

Cov.:

AF XY:

0.0309

AC XY:

2300

AN XY:

74412

show subpopulations

African (AFR)

AF:

0.104

AC:

4308

AN:

41532

American (AMR)

AF:

0.0113

AC:

173

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0346

AC:

120

AN:

3470

East Asian (EAS)

AF:

0.0141

AC:

AN:

5168

South Asian (SAS)

AF:

0.00393

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10604

Middle Eastern (MID)

AF:

0.0308

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00128

AC:

AN:

67976

Other (OTH)

AF:

0.0246

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

241

482

724

965

1206

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

150

200

250

<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:

0.0315

Hom.:

Bravo

AF:

0.0367

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

BayesDel_noAF

Benign

-0.81

CADD

Benign

6.2

(source)

DANN

Benign

0.67

PhyloP100

0.73

PromoterAI

-0.070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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

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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