rs8177877

Positions:

• chr16-81090611-T-C

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.218A>G​(p.Asn73Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00813 in 1,600,706 control chromosomes in the GnomAD database, including 513 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.035 (248 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (265 hom.)
• Consequence: GCSH NM_004483.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.12

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.003116995).
• BP6: Variant 16-81090611-T-C is Benign according to our data. Variant chr16-81090611-T-C is described in ClinVar as [Benign]. Clinvar id is 462901.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr16-81090611-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.111 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GCSH	NM_004483.5	c.218A>G	p.Asn73Ser	missense_variant	2/5	ENST00000315467.9	NP_004474.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GCSH	ENST00000315467.9	c.218A>G	p.Asn73Ser	missense_variant	2/5	1	NM_004483.5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1	c.218A>G	p.Asn73Ser	missense_variant	2/6	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2	c.218A>G	p.Asn73Ser	missense_variant	2/6	5		ENSP00000491651.1

Frequencies

GnomAD3 genomes AF: 0.0347 AC: 5280 AN: 152080 Hom.: 247 Cov.: 32

Gnomad AFR AF: 0.114

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.0349

Gnomad EAS AF: 0.0141

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.00144

Gnomad OTH AF: 0.0268

GnomAD3 exomes AF: 0.0117 AC: 2947 AN: 251428 Hom.: 113 AF XY: 0.00951 AC XY: 1292 AN XY: 135910

Gnomad AFR exome AF: 0.115

Gnomad AMR exome AF: 0.00671

Gnomad ASJ exome AF: 0.0331

Gnomad EAS exome AF: 0.00946

Gnomad SAS exome AF: 0.00258

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.00176

Gnomad OTH exome AF: 0.00880

GnomAD4 exome AF: 0.00532 AC: 7713 AN: 1448508 Hom.: 265 Cov.: 28 AF XY: 0.00496 AC XY: 3577 AN XY: 721616

Gnomad4 AFR exome AF: 0.114

Gnomad4 AMR exome AF: 0.00796

Gnomad4 ASJ exome AF: 0.0327

Gnomad4 EAS exome AF: 0.0158

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.000112

Gnomad4 NFE exome AF: 0.000910

Gnomad4 OTH exome AF: 0.0125

GnomAD4 genome AF: 0.0348 AC: 5298 AN: 152198 Hom.: 248 Cov.: 32 AF XY: 0.0336 AC XY: 2499 AN XY: 74422

Gnomad4 AFR AF: 0.114

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.0349

Gnomad4 EAS AF: 0.0143

Gnomad4 SAS AF: 0.00436

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00144

Gnomad4 OTH AF: 0.0265

Alfa AF: 0.00964 Hom.: 96

Bravo AF: 0.0408

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.107 AC: 469

ESP6500EA AF: 0.00372 AC: 32

ExAC AF: 0.0137 AC: 1658

Asia WGS AF: 0.0160 AC: 58 AN: 3478

EpiCase AF: 0.00316

EpiControl AF: 0.00273

ClinVar

Significance: Benign

Submissions summary: Benign:3

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	-	- -

Glycine encephalopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.62	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	.;.;.;T;.
Eigen	Benign	-0.059
Eigen_PC	Benign	0.15
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D;D;D
MetaRNN	Benign	0.0031	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.88	.;.;.;L;.
PrimateAI	Benign	0.40	T
PROVEAN	Uncertain	-3.1	.;.;.;D;.
REVEL	Benign	0.052
Sift	Benign	0.24	.;.;.;T;.
Sift4G	Benign	0.23	.;.;.;T;.
Polyphen		0.0040	.;.;.;B;.
Vest4		0.082
MPC		0.32
ClinPred		0.034	T
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.41
gMVP		0.52

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: rs8177877; hg19: chr16-81124216; COSMIC: COSV59602107;