NM_004483.5:c.62C>T

Variant names:

Variant summary

Our verdict is Benign. Variant got -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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 links:

ENSG00000284512 (HGNC:):

ENSG00000284512 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 1164317.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81096217-G-A is described in Lovd as [Benign].

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	UniProt
GCSH	NM_004483.5 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2	P23434
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	UniProt
GCSH	ENST00000315467.9 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3	P23434
ENSG00000284512	ENST00000640345.1 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 6	5		ENSP00000492798.1	A0A1W2PS29
ENSG00000260643	ENST00000564536.2 link	c.62C>T	p.Ser21Leu	missense_variant	Exon 1 of 6	5		ENSP00000491651.1	A0A1W2PPQ1

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

GnomAD3 exomes

AF:

0.540

AC:

696

AN:

1288

Hom.:

AF XY:

0.552

AC XY:

428

AN XY:

776

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 SAS exome

AF:

0.538

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

Gnomad4 AFR exome

AF:

0.481

Gnomad4 AMR exome

AF:

0.789

Gnomad4 ASJ exome

AF:

0.795

Gnomad4 EAS exome

AF:

0.703

Gnomad4 SAS exome

AF:

0.603

Gnomad4 FIN exome

AF:

0.803

Gnomad4 NFE exome

AF:

0.635

Gnomad4 OTH exome

AF:

0.678

GnomAD4 genome

AF:

0.797

AC:

118945

AN:

149294

Hom.:

48741

Cov.:

AF XY:

0.793

AC XY:

57799

AN XY:

72908

show subpopulations

Gnomad4 AFR

AF:

0.576

Gnomad4 AMR

AF:

0.844

Gnomad4 ASJ

AF:

0.919

Gnomad4 EAS

AF:

0.726

Gnomad4 SAS

AF:

0.828

Gnomad4 FIN

AF:

0.821

Gnomad4 NFE

AF:

0.911

Gnomad4 OTH

AF:

0.833

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

DANN

Benign

0.80

DEOGEN2

Benign

0.062

.;.;.;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

0.34

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

PrimateAI

Uncertain

0.75

PROVEAN

Benign

-0.23

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

REVEL

Benign

0.021

Sift

Benign

0.71

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

Sift4G

Benign

0.50

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

Polyphen

0.0

.;.;.;B;.;.;.

Vest4

0.070

MPC

0.34

ClinPred

0.0071

GERP RS

0.18

Varity_R

0.039

gMVP

0.33

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over