Genetic Variant GCSH:c.293-10_293-9dupTT (chr16-81084602-G-GAA) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004483.5(GCSH):c.293-10_293-9dupTT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000666 in 150,102 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000067 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

GCSH
NM_004483.5 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.13

Publications

0 publications found

Variant links:

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

GCSH links:

ENSG00000284512 (HGNC:):

ENSG00000284512 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GCSH	NM_004483.5 link	c.293-10_293-9dupTT		intron_variant	Intron 3 of 4	ENST00000315467.9	NP_004474.2	P23434

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
GCSH	ENST00000315467.9 link	c.293-9_293-8insTT	intron_variant	Intron 3 of 4	1	NM_004483.5	ENSP00000319531.3	P23434
ENSG00000284512	ENST00000640345.1 link	c.293-9_293-8insTT	intron_variant	Intron 3 of 5	5		ENSP00000492798.1	A0A1W2PS29
ENSG00000260643	ENST00000564536.2 link	c.293-9_293-8insTT	intron_variant	Intron 3 of 5	5		ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes

AF:

0.00000666

AC:

AN:

150102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000245

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1443272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

718434

African (AFR)

AF:

0.00

AC:

AN:

32842

American (AMR)

AF:

0.00

AC:

AN:

43884

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25858

East Asian (EAS)

AF:

0.00

AC:

AN:

39480

South Asian (SAS)

AF:

0.00

AC:

AN:

84876

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53154

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5718

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1097842

Other (OTH)

AF:

0.00

AC:

AN:

59618

GnomAD4 genome

AF:

0.00000666

AC:

AN:

150102

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73024

show subpopulations

African (AFR)

AF:

0.0000245

AC:

AN:

40860

American (AMR)

AF:

0.00

AC:

AN:

15096

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3462

East Asian (EAS)

AF:

0.00

AC:

AN:

5152

South Asian (SAS)

AF:

0.00

AC:

AN:

4796

European-Finnish (FIN)

AF:

0.00

AC:

AN:

9798

Middle Eastern (MID)

AF:

0.00

AC:

AN:

312

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67656

Other (OTH)

AF:

0.00

AC:

AN:

2062

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

PhyloP100

1.1

Splicing

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

Publications

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16-81084602-GAA-GAAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over