rs8052579

Positions:

• chr16-81096217-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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 same amino acid change has been previously reported as Likely benignin 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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.564

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]

ACMG classification

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/exons	MANE	Protein	UniProt
GCSH	NM_004483.5	c.62C>T	p.Ser21Leu	missense_variant	1/5	ENST00000315467.9	NP_004474.2
GCSH	XM_017023136.3	c.62C>T	p.Ser21Leu	missense_variant	1/5		XP_016878625.1
GCSH	NR_033249.2	n.179C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCSH	ENST00000315467.9	c.62C>T	p.Ser21Leu	missense_variant	1/5	1	NM_004483.5	ENSP00000319531	P1

Frequencies

GnomAD3 genomes AF: 0.797 AC: 118919 AN: 149186 Hom.: 48732 Cov.: 34

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.: 61 AF XY: 0.552 AC XY: 428 AN XY: 776

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.: 32 AF XY: 0.647 AC XY: 327531 AN XY: 506550

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.: 34 AF XY: 0.793 AC XY: 57799 AN XY: 72908

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

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 04, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Non-ketotic hyperglycinemia Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -

GCSH-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 25, 2020

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	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.80
DEOGEN2	Benign	0.062	.;.;.;T;.;.;.
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.044	N
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	T
MutationAssessor	Benign	0.34	.;.;.;N;.;.;.
MutationTaster	Benign	1.0	P;P
PrimateAI	Uncertain	0.75	T
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	T
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

Other links and lift over

dbSNP: rs8052579; hg19: chr16-81129822; COSMIC: COSV59601803; COSMIC: COSV59601803;