chr16-81087592-A-C

Variant names:

• chr16-81087592-A-C
• rs8177909
• NM_004483.5:c.292+9T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004483.5(GCSH):​c.292+9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00097 in 1,572,096 control chromosomes in the GnomAD database, including 15 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0053 (8 hom., cov: 32)
  • Exomes 𝑓: 0.00051 (7 hom.)
• Consequence: GCSH NM_004483.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.675
• Publications: 1 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 16-81087592-A-C is Benign according to our data. Variant chr16-81087592-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 462904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00526 (801/152222) while in subpopulation AFR AF = 0.0186 (773/41518). AF 95% confidence interval is 0.0175. There are 8 homozygotes in GnomAd4. There are 391 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 AR,Unknown gene

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.292+9T>G		intron	N/A	NP_004474.2
	GCSH	NR_033249.2		n.346-2998T>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	ENST00000315467.9	TSL:1 MANE Select	c.292+9T>G		intron	N/A	ENSP00000319531.3	P23434
	ENSG00000284512	ENST00000640345.1	TSL:5	c.292+9T>G		intron	N/A	ENSP00000492798.1	A0A1W2PS29
	ENSG00000260643	ENST00000564536.2	TSL:5	c.292+9T>G		intron	N/A	ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes AF: 0.00527 AC: 802 AN: 152108 Hom.: 8 Cov.: 32

Gnomad AFR AF: 0.0187

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00124

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: 0.0000735

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00142 AC: 356 AN: 251184 AF XY: 0.00111

Gnomad AFR exome AF: 0.0201

Gnomad AMR exome AF: 0.000752

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000510 AC: 724 AN: 1419874 Hom.: 7 Cov.: 28 AF XY: 0.000455 AC XY: 323 AN XY: 709166

African (AFR) AF: 0.0183 AC: 590 AN: 32200

American (AMR) AF: 0.000940 AC: 42 AN: 44674

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25824

East Asian (EAS) AF: 0.00 AC: 0 AN: 39486

South Asian (SAS) AF: 0.0000234 AC: 2 AN: 85378

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53302

Middle Eastern (MID) AF: 0.00242 AC: 13 AN: 5364

European-Non Finnish (NFE) AF: 0.0000177 AC: 19 AN: 1074688

Other (OTH) AF: 0.000984 AC: 58 AN: 58958

GnomAD4 genome AF: 0.00526 AC: 801 AN: 152222 Hom.: 8 Cov.: 32 AF XY: 0.00525 AC XY: 391 AN XY: 74442

African (AFR) AF: 0.0186 AC: 773 AN: 41518

American (AMR) AF: 0.00124 AC: 19 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00215 Hom.: 5

Bravo AF: 0.00586

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glycine encephalopathy (2)
-	-	1	GCSH-related disorder (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	8.0
DANN	Benign	0.56
PhyloP100		0.68
Mutation Taster		=100/0	polymorphism

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: rs8177909; hg19: chr16-81121197;