rs8177876

chr16-81090670-G-A

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_004483.5(GCSH):c.159C>T(p.Phe53=) variant causes a synonymous change. The variant allele was found at a frequency of 0.0657 in 1,609,126 control chromosomes in the GnomAD database, including 4,042 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.057 (257 hom., cov: 32)
  • Exomes 𝑓: 0.067 (3785 hom.)
• Consequence: GCSH NM_004483.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 4.11

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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.39).
• BP6: Variant 16-81090670-G-A is Benign according to our data. Variant chr16-81090670-G-A is described in ClinVar as [Benign]. Clinvar id is 1166773.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81090670-G-A is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0717 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCSH	NM_004483.5	c.159C>T	p.Phe53=	synonymous_variant	2/5	ENST00000315467.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCSH	ENST00000315467.9	c.159C>T	p.Phe53=	synonymous_variant	2/5	1	NM_004483.5	P1

Frequencies

GnomAD3 genomes AF: 0.0571 AC: 8686 AN: 152074 Hom.: 255 Cov.: 32

Gnomad AFR AF: 0.0352

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.0482

Gnomad ASJ AF: 0.0291

Gnomad EAS AF: 0.00115

Gnomad SAS AF: 0.0247

Gnomad FIN AF: 0.108

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0734

Gnomad OTH AF: 0.0506

GnomAD3 exomes AF: 0.0540 AC: 13570 AN: 251404 Hom.: 527 AF XY: 0.0541 AC XY: 7357 AN XY: 135900

Gnomad AFR exome AF: 0.0391

Gnomad AMR exome AF: 0.0265

Gnomad ASJ exome AF: 0.0300

Gnomad EAS exome AF: 0.00114

Gnomad SAS exome AF: 0.0248

Gnomad FIN exome AF: 0.107

Gnomad NFE exome AF: 0.0728

Gnomad OTH exome AF: 0.0554

GnomAD4 exome AF: 0.0666 AC: 96966 AN: 1456934 Hom.: 3785 Cov.: 29 AF XY: 0.0652 AC XY: 47297 AN XY: 725144

Gnomad4 AFR exome AF: 0.0336

Gnomad4 AMR exome AF: 0.0286

Gnomad4 ASJ exome AF: 0.0295

Gnomad4 EAS exome AF: 0.000504

Gnomad4 SAS exome AF: 0.0256

Gnomad4 FIN exome AF: 0.105

Gnomad4 NFE exome AF: 0.0742

Gnomad4 OTH exome AF: 0.0598

GnomAD4 genome AF: 0.0572 AC: 8698 AN: 152192 Hom.: 257 Cov.: 32 AF XY: 0.0575 AC XY: 4279 AN XY: 74396

Gnomad4 AFR AF: 0.0354

Gnomad4 AMR AF: 0.0482

Gnomad4 ASJ AF: 0.0291

Gnomad4 EAS AF: 0.00116

Gnomad4 SAS AF: 0.0241

Gnomad4 FIN AF: 0.108

Gnomad4 NFE AF: 0.0734

Gnomad4 OTH AF: 0.0520

Alfa AF: 0.0676 Hom.: 413

Bravo AF: 0.0514

Asia WGS AF: 0.0170 AC: 60 AN: 3478

EpiCase AF: 0.0682

EpiControl AF: 0.0666

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Non-ketotic hyperglycinemia Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.39
Cadd	Benign	13
Dann	Benign	0.86

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs8177876; hg19: chr16-81124275;