rs1443267686

Variant names:

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

Your query was ambiguous. Multiple possible variants found:

• chr16-81096202-C-A
• chr16-81096202-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C26Y) has been classified as Uncertain significance.

• 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
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
• 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 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

GnomAD2 exomes AF: 0.00 AC: 0 AN: 3820 AF XY: 0.00

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 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: 8.57e-7 AC: 1 AN: 1166506 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 564828

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000425 AC: 1 AN: 23504

American (AMR) AF: 0.00 AC: 0 AN: 9644

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15808

East Asian (EAS) AF: 0.00 AC: 0 AN: 27078

South Asian (SAS) AF: 0.00 AC: 0 AN: 41392

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 26820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3184

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 971790

Other (OTH) AF: 0.00 AC: 0 AN: 47286

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

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;.;.;.
PhyloP100		1.5
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
PromoterAI		0.010	Neutral
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

Other links and lift over

dbSNP: rs1443267686; hg19: chr16-81129807;