rs775381594

Variant names:

• chr16-81096195-C-T
• rs775381594
• NM_004483.5:c.84G>A

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 2P and 13B. PM2 BP4_Strong BP6_Very_Strong BP7

The NM_004483.5(GCSH):​c.84G>A​(p.Pro28Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000395 in 151,824 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 34)
  • Exomes 𝑓: 0.035 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GCSH NM_004483.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.151
• Publications: 3 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 -11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 16-81096195-C-T is Benign according to our data. Variant chr16-81096195-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 531790.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.151 with no splicing effect.

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.84G>A	p.Pro28Pro	synonymous	Exon 1 of 5	NP_004474.2
	GCSH	NR_033249.2		n.201G>A		non_coding_transcript_exon	Exon 1 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	ENST00000315467.9	TSL:1 MANE Select	c.84G>A	p.Pro28Pro	synonymous	Exon 1 of 5	ENSP00000319531.3	P23434
	ENSG00000284512	ENST00000640345.1	TSL:5	c.84G>A	p.Pro28Pro	synonymous	Exon 1 of 6	ENSP00000492798.1	A0A1W2PS29
	ENSG00000260643	ENST00000564536.2	TSL:5	c.84G>A	p.Pro28Pro	synonymous	Exon 1 of 6	ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes AF: 0.0000395 AC: 6 AN: 151824 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.0000242

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: 0.000189

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000442

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.129 AC: 530 AN: 4124 AF XY: 0.133

Gnomad AFR exome AF: 0.151

Gnomad AMR exome AF: 0.0764

Gnomad ASJ exome AF: 0.127

Gnomad EAS exome AF: 0.0698

Gnomad FIN exome AF: 0.128

Gnomad NFE exome AF: 0.177

Gnomad OTH exome AF: 0.162

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.0350 AC: 32961 AN: 941686 Hom.: 0 Cov.: 32 AF XY: 0.0351 AC XY: 16094 AN XY: 458366

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

African (AFR) AF: 0.0221 AC: 442 AN: 19980

American (AMR) AF: 0.0125 AC: 118 AN: 9466

Ashkenazi Jewish (ASJ) AF: 0.0156 AC: 222 AN: 14194

East Asian (EAS) AF: 0.00258 AC: 68 AN: 26378

South Asian (SAS) AF: 0.0280 AC: 988 AN: 35306

European-Finnish (FIN) AF: 0.00882 AC: 228 AN: 25856

Middle Eastern (MID) AF: 0.0206 AC: 58 AN: 2810

European-Non Finnish (NFE) AF: 0.0388 AC: 29807 AN: 767292

Other (OTH) AF: 0.0255 AC: 1030 AN: 40404

⚠️ 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 AF: 0.0000395 AC: 6 AN: 151824 Hom.: 0 Cov.: 34 AF XY: 0.0000135 AC XY: 1 AN XY: 74168

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

African (AFR) AF: 0.0000242 AC: 1 AN: 41372

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.000189 AC: 2 AN: 10566

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000442 AC: 3 AN: 67858

Other (OTH) AF: 0.00 AC: 0 AN: 2086

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00615 Hom.: 0

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	8.6
DANN	Benign	0.88
PhyloP100		-0.15
PromoterAI		-0.0098	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs775381594; hg19: chr16-81129800; COSMIC: COSV59601784; COSMIC: COSV59601784;