16-81096202-C-A

Variant names:

• chr16-81096202-C-A
• rs1443267686
• NM_004483.5:c.77G>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_004483.5(GCSH):​c.77G>T​(p.Cys26Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 8.6e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCSH NM_004483.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.46

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20101213).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5	c.77G>T	p.Cys26Phe	missense_variant	Exon 1 of 5	ENST00000315467.9	NP_004474.2
GCSH	XM_017023136.3	c.77G>T	p.Cys26Phe	missense_variant	Exon 1 of 5		XP_016878625.1
GCSH	NR_033249.2	n.194G>T		non_coding_transcript_exon_variant	Exon 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GCSH	ENST00000315467.9	c.77G>T	p.Cys26Phe	missense_variant	Exon 1 of 5	1	NM_004483.5	ENSP00000319531.3
ENSG00000284512	ENST00000640345.1	c.77G>T	p.Cys26Phe	missense_variant	Exon 1 of 6	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2	c.77G>T	p.Cys26Phe	missense_variant	Exon 1 of 6	5		ENSP00000491651.1

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 8.57e-7 AC: 1 AN: 1166506 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 564828

Gnomad4 AFR exome AF: 0.0000425

Gnomad4 AMR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Benign	0.91
DEOGEN2	Benign	0.13	.;.;.;T;.;.;.
Eigen	Benign	-0.63
Eigen_PC	Benign	-0.66
FATHMM_MKL	Benign	0.097	N
LIST_S2	Benign	0.59	T;T;T;T;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.20	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.4	.;.;.;M;.;.;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Uncertain	-2.6	.;.;.;D;.;.;.
REVEL	Benign	0.097
Sift	Benign	0.072	.;.;.;T;.;.;.
Sift4G	Uncertain	0.042	.;.;.;D;.;.;.
Polyphen		0.64	.;.;.;P;.;.;.
Vest4		0.25
MutPred		0.32		Loss of catalytic residue at P25 (P = 0.0889);.;Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);Loss of catalytic residue at P25 (P = 0.0889);.;
MVP		0.14
MPC		0.65
ClinPred		0.38	T
GERP RS		3.5
Varity_R		0.31
gMVP		0.53

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: rs1443267686; hg19: chr16-81129807;