16-81096202-C-T

Variant names:

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_004483.5(GCSH):c.77G>A(p.Cys26Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000129 in 1,318,712 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 Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

GCSH
NM_004483.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 1.46

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: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0845944).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
GCSH	NM_004483.5 link	c.77G>A	p.Cys26Tyr	missense_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2
GCSH	XM_017023136.3 link	c.77G>A	p.Cys26Tyr	missense_variant	Exon 1 of 5		XP_016878625.1
GCSH	NR_033249.2 link	n.194G>A		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.77G>A	p.Cys26Tyr	missense_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1 link	c.77G>A	p.Cys26Tyr	missense_variant	Exon 1 of 6	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2 link	c.77G>A	p.Cys26Tyr	missense_variant	Exon 1 of 6	5		ENSP00000491651.1

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152104

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000524

AC:

AN:

3820

AF XY:

0.000415

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00158

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:

0.0000103

AC:

AN:

1166500

Hom.:

Cov.:

AF XY:

0.00000885

AC XY:

AN XY:

564828

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.0000425

AC:

AN:

23504

American (AMR)

AF:

0.000104

AC:

AN:

9644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15808

East Asian (EAS)

AF:

0.00

AC:

AN:

27078

South Asian (SAS)

AF:

0.00

AC:

AN:

41394

European-Finnish (FIN)

AF:

0.00

AC:

AN:

26820

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3184

European-Non Finnish (NFE)

AF:

0.00000617

AC:

AN:

971782

Other (OTH)

AF:

0.0000846

AC:

AN:

47286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000000000461853), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.358

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:

0.0000328

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.0000722

AC:

AN:

41570

American (AMR)

AF:

0.0000654

AC:

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10594

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67972

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.563

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:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Sep 04, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.77G>A (p.C26Y) alteration is located in exon 1 (coding exon 1) of the GCSH gene. This alteration results from a G to A substitution at nucleotide position 77, causing the cysteine (C) at amino acid position 26 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Glycine encephalopathy

Uncertain:1

Apr 16, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with a GCSH-related disease. This sequence change replaces cysteine with tyrosine at codon 26 of the GCSH protein (p.Cys26Tyr). The cysteine residue is weakly conserved and there is a large physicochemical difference between cysteine and tyrosine. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.41

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.40

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

Eigen

Benign

-0.64

Eigen_PC

Benign

-0.68

FATHMM_MKL

Benign

0.038

LIST_S2

Benign

0.83

T;T;T;T;D;T;D

M_CAP

Pathogenic

0.32

MetaRNN

Benign

0.085

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

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.4

.;.;.;M;.;.;.

PhyloP100

1.5

PrimateAI

Pathogenic

0.83

PROVEAN

Uncertain

-3.3

.;.;.;D;.;.;.

REVEL

Benign

0.092

Sift

Benign

0.055

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

Sift4G

Uncertain

0.045

.;.;.;D;.;.;.

Polyphen

0.84

.;.;.;P;.;.;.

Vest4

0.18

MutPred

0.33

Loss of catalytic residue at P25 (P = 0.0889);.;Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);.;

MVP

0.16

MPC

0.66

ClinPred

0.13

GERP RS

3.5

PromoterAI

0.051

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.28

gMVP

0.58

Mutation Taster

=88/12

polymorphism

(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