rs10514515

Variant names:

• chr16-81081717-T-C
• rs10514515
• ENST00000640345.1:c.424+2746A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The ENST00000640345.1(ENSG00000284512):​c.424+2746A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,216 control chromosomes in the GnomAD database, including 988 homozygotes. 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: 𝑓 0.11 (988 hom., cov: 29)
• Consequence: ENSG00000284512 ENST00000640345.1 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.44
• Publications: 6 publications found

Genes affected

ENSG00000284512 (HGNC:):

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.197 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5	c.*1149A>G		downstream_gene_variant		ENST00000315467.9	NP_004474.2
GCSH	NR_033249.2	n.*228A>G		downstream_gene_variant
GCSH	XM_047433900.1	c.*1149A>G		downstream_gene_variant			XP_047289856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ENSG00000284512	ENST00000640345.1	c.424+2746A>G		intron_variant	Intron 4 of 5	5		ENSP00000492798.1
ENSG00000260643	ENST00000564536.2	c.424+2746A>G		intron_variant	Intron 4 of 5	5		ENSP00000491651.1
GCSH	ENST00000315467.9	c.*1149A>G		downstream_gene_variant		1	NM_004483.5	ENSP00000319531.3

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16863 AN: 152098 Hom.: 986 Cov.: 29

Gnomad AFR AF: 0.157

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.116

Gnomad ASJ AF: 0.0778

Gnomad EAS AF: 0.208

Gnomad SAS AF: 0.104

Gnomad FIN AF: 0.120

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0772

Gnomad OTH AF: 0.0963

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.111 AC: 16887 AN: 152216 Hom.: 988 Cov.: 29 AF XY: 0.113 AC XY: 8404 AN XY: 74432

African (AFR) AF: 0.157 AC: 6514 AN: 41512

American (AMR) AF: 0.116 AC: 1772 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0778 AC: 270 AN: 3470

East Asian (EAS) AF: 0.207 AC: 1073 AN: 5182

South Asian (SAS) AF: 0.102 AC: 492 AN: 4822

European-Finnish (FIN) AF: 0.120 AC: 1276 AN: 10604

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0772 AC: 5249 AN: 68020

Other (OTH) AF: 0.0981 AC: 207 AN: 2110

Alfa AF: 0.100 Hom.: 112

Bravo AF: 0.116

Asia WGS AF: 0.151 AC: 525 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	9.6
DANN	Benign	0.87
PhyloP100		1.4

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs10514515; hg19: chr16-81115322;