16-81082963-C-G

Variant names:

• chr16-81082963-C-G
• rs746937065
• NM_004483.5:c.425G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_004483.5(GCSH):​c.425G>C​(p.Gly142Ala) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G142V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCSH NM_004483.5 missense, splice_region
• Scores: Splicing: ADA: 0.9993
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.79
• Publications: 0 publications found

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]

GCSH Gene-Disease associations (from GenCC):

• glycine encephalopathy

  Inheritance: AR Classification: STRONG, LIMITED Submitted by: ClinGen, Ambry Genetics
• multiple mitochondrial dysfunctions syndrome 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• infantile glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• neonatal glycine encephalopathy

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• atypical glycine encephalopathy

  Inheritance: Unknown Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000284512 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004483.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	NM_004483.5	MANE Select	c.425G>C	p.Gly142Ala	missense splice_region	Exon 5 of 5	NP_004474.2
	GCSH	NR_033249.2		n.478G>C		splice_region non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	ENST00000315467.9	TSL:1 MANE Select	c.425G>C	p.Gly142Ala	missense splice_region	Exon 5 of 5	ENSP00000319531.3	P23434
	ENSG00000284512	ENST00000640345.1	TSL:5	c.424+1500G>C		intron	N/A	ENSP00000492798.1	A0A1W2PS29
	ENSG00000260643	ENST00000564536.2	TSL:5	c.424+1500G>C		intron	N/A	ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251078 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 7.03e-7 AC: 1 AN: 1422234 Hom.: 0 Cov.: 25 AF XY: 0.00000141 AC XY: 1 AN XY: 710140

African (AFR) AF: 0.00 AC: 0 AN: 32670

American (AMR) AF: 0.0000224 AC: 1 AN: 44654

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25888

East Asian (EAS) AF: 0.00 AC: 0 AN: 39436

South Asian (SAS) AF: 0.00 AC: 0 AN: 85480

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53396

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1076038

Other (OTH) AF: 0.00 AC: 0 AN: 58972

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.38	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Uncertain	0.18	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	2.0	M
PhyloP100		7.8
PrimateAI	Uncertain	0.54	T
PROVEAN	Pathogenic	-5.7	D
REVEL	Pathogenic	0.67
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.041	D
Polyphen		1.0	D
Vest4		0.84
MutPred		0.93		Gain of catalytic residue at G142 (P = 0.0528)
MVP		0.90
MPC		1.0
ClinPred		0.99	D
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.77
gMVP		0.65

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.99
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

Other links and lift over

dbSNP: rs746937065; hg19: chr16-81116568;