rs958918692

Variant names:

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_StrongBP6_ModerateBP7BS1

The NM_004483.5(GCSH):c.75C>T(p.Pro25Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 1,318,378 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000011 ( 0 hom. )

Consequence

GCSH
NM_004483.5 synonymous

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.241

Publications

0 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 -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 16-81096204-G-A is Benign according to our data. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr16-81096204-G-A is described in CliVar as Likely_benign. Clinvar id is 531789.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=-0.241 with no splicing effect.

BS1

Variant frequency is greater than expected in population afr. GnomAdExome4 allele frequency = 0.0000111 (13/1166186) while in subpopulation AFR AF = 0.000256 (6/23454). AF 95% confidence interval is 0.00011. There are 0 homozygotes in GnomAdExome4. There are 3 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5 link	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2	P23434
GCSH	XM_017023136.3 link	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 5		XP_016878625.1
GCSH	NR_033249.2 link	n.192C>T		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.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3	P23434
ENSG00000284512	ENST00000640345.1 link	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 6	5		ENSP00000492798.1	A0A1W2PS29
ENSG00000260643	ENST00000564536.2 link	c.75C>T	p.Pro25Pro	synonymous_variant	Exon 1 of 6	5		ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152084

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00

AC:

AN:

2228

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000111

AC:

AN:

1166186

Hom.:

Cov.:

AF XY:

0.00000531

AC XY:

AN XY:

564696

show subpopulations

African (AFR)

AF:

0.000256

AC:

AN:

23454

American (AMR)

AF:

0.00

AC:

AN:

9332

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15734

East Asian (EAS)

AF:

0.00

AC:

AN:

27076

South Asian (SAS)

AF:

0.00

AC:

AN:

41358

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26834

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3174

European-Non Finnish (NFE)

AF:

0.00000206

AC:

AN:

971942

Other (OTH)

AF:

0.000106

AC:

AN:

47282

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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:

0.0000197

AC:

AN:

152192

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.0000481

AC:

AN:

41560

American (AMR)

AF:

0.00

AC:

AN:

15288

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5168

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67964

Other (OTH)

AF:

0.00

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.450

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<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:

0.00

Hom.:

Bravo

AF:

0.00000756

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Glycine encephalopathy

Benign:1

Jun 04, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely 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

-0.78

CADD

Benign

7.6

(source)

DANN

Benign

0.90

PhyloP100

-0.24

PromoterAI

-0.0082

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

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