rs540997326

chr16-81096226-G-Achr16-81096226-G-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004483.5(GCSH):c.53C>T(p.Ala18Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00375 in 1,314,560 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0031 (4 hom., cov: 33)
  • Exomes 𝑓: 0.0038 (4 hom.)
• Consequence: GCSH NM_004483.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 0.391

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 -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0038013756).
• BP6: Variant 16-81096226-G-A is Benign according to our data. Variant chr16-81096226-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 462908.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}. Variant chr16-81096226-G-A is described in Lovd as [Benign].
• BS2: High Homozygotes in GnomAd at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GCSH	NM_004483.5	c.53C>T	p.Ala18Val	missense_variant	1/5	ENST00000315467.9
GCSH	XM_017023136.3	c.53C>T	p.Ala18Val	missense_variant	1/5
GCSH	NR_033249.2	n.170C>T		non_coding_transcript_exon_variant	1/4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GCSH	ENST00000315467.9	c.53C>T	p.Ala18Val	missense_variant	1/5	1	NM_004483.5	P1

Frequencies

GnomAD3 genomes AF: 0.00311 AC: 473 AN: 152036 Hom.: 4 Cov.: 33

Gnomad AFR AF: 0.000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00242

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0103

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00424

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.00215 AC: 2 AN: 930 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 614

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0435

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00383 AC: 4452 AN: 1162416 Hom.: 4 Cov.: 27 AF XY: 0.00373 AC XY: 2098 AN XY: 562830

Gnomad4 AFR exome AF: 0.000430

Gnomad4 AMR exome AF: 0.00155

Gnomad4 ASJ exome AF: 0.000899

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0104

Gnomad4 NFE exome AF: 0.00413

Gnomad4 OTH exome AF: 0.00274

GnomAD4 genome AF: 0.00311 AC: 473 AN: 152144 Hom.: 4 Cov.: 33 AF XY: 0.00335 AC XY: 249 AN XY: 74386

Gnomad4 AFR AF: 0.000722

Gnomad4 AMR AF: 0.00242

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0103

Gnomad4 NFE AF: 0.00424

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.00276 Hom.: 0

Bravo AF: 0.00271

ExAC AF: 0.000338 AC: 4

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Non-ketotic hyperglycinemia Uncertain:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Nov 29, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Oct 31, 2018	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.52
Cadd	Benign	13
Dann	Benign	0.96
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.029	N
LIST_S2	Benign	0.47	T;T;T;T;T;T;T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0038	T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N
PrimateAI	Uncertain	0.74	T
Polyphen		0.0020	.;.;.;B;.;.;.
Vest4		0.070
MVP		0.19
MPC		0.38
ClinPred		0.044	T
GERP RS		-1.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.040
gMVP		0.35

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: rs540997326; hg19: chr16-81129831; COSMIC: COSV59601740; COSMIC: COSV59601740;