16-81082874-C-T

Variant names:

• chr16-81082874-C-T
• rs760566469
• NM_004483.5:c.514G>A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_004483.5(GCSH):​c.514G>A​(p.Glu172Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000899 in 1,112,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000090 (0 hom.)
• Consequence: GCSH NM_004483.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.86

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]

ENSG00000284512 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5	c.514G>A	p.Glu172Lys	missense_variant	Exon 5 of 5	ENST00000315467.9	NP_004474.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCSH	ENST00000315467.9	c.514G>A	p.Glu172Lys	missense_variant	Exon 5 of 5	1	NM_004483.5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1	c.424+1589G>A		intron_variant	Intron 4 of 5	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2	c.424+1589G>A		intron_variant	Intron 4 of 5	5		ENSP00000491651.1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD3 exomes AF: 0.0000240 AC: 6 AN: 250400 Hom.: 0 AF XY: 0.0000295 AC XY: 4 AN XY: 135520

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS 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: 0.00000899 AC: 10 AN: 1112672 Hom.: 0 Cov.: 16 AF XY: 0.0000105 AC XY: 6 AN XY: 569650

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000136

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000504

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 27

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycine encephalopathy Uncertain:1

Oct 26, 2020

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamic acid with lysine at codon 172 of the GCSH protein (p.Glu172Lys). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and lysine. The frequency data for this variant in the population databases is considered 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 GCSH-related conditions. 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 and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.64
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T;.
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.017	T
MetaRNN	Uncertain	0.49	T;T
MetaSVM	Benign	-0.88	T
MutationAssessor	Uncertain	2.7	M;.
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.1	D;.
REVEL	Benign	0.17
Sift	Benign	0.034	D;.
Sift4G	Uncertain	0.025	D;.
Polyphen		0.69	P;.
Vest4		0.52
MutPred		0.32		Gain of methylation at E172 (P = 0.0037);.;
MVP		0.53
MPC		0.53
ClinPred		0.74	D
GERP RS		5.4
Varity_R		0.45
gMVP		0.55

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: rs760566469; hg19: chr16-81116479;