rs775381594

chr16-81096195-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_004483.5(GCSH):c.84G>A(p.Pro28=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 151,824 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 34)
  • Exomes 𝑓: 0.035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCSH NM_004483.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.151

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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-81096195-C-T is Benign according to our data. Variant chr16-81096195-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 531790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81096195-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCSH	NM_004483.5	c.84G>A	p.Pro28=	synonymous_variant	1/5	ENST00000315467.9
GCSH	XM_017023136.3	c.84G>A	p.Pro28=	synonymous_variant	1/5
GCSH	NR_033249.2	n.201G>A		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCSH	ENST00000315467.9	c.84G>A	p.Pro28=	synonymous_variant	1/5	1	NM_004483.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151824 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.129 AC: 530 AN: 4124 Hom.: 0 AF XY: 0.133 AC XY: 342 AN XY: 2566

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0764

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0698

Gnomad SAS exome AF: 0.0970

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.162

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0350 AC: 32961 AN: 941686 Hom.: 0 Cov.: 32 AF XY: 0.0351 AC XY: 16094 AN XY: 458366

Gnomad4 AFR exome AF: 0.0221

Gnomad4 AMR exome AF: 0.0125

Gnomad4 ASJ exome AF: 0.0156

Gnomad4 EAS exome AF: 0.00258

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.00882

Gnomad4 NFE exome AF: 0.0388

Gnomad4 OTH exome AF: 0.0255

GnomAD4 genome AF: 0.0000395 AC: 6 AN: 151824 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000189

Gnomad4 NFE AF: 0.0000442

Gnomad4 OTH AF: 0.00

Alfa AF: 0.00615 Hom.: 0

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 04, 2021

- -

Non-ketotic hyperglycinemia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 15, 2021

- -

GCSH-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 05, 2019

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
BayesDel_noAF	Benign	-0.64
Cadd	Benign	8.6
Dann	Benign	0.88
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs775381594; hg19: chr16-81129800; COSMIC: COSV59601784; COSMIC: COSV59601784;