16-81084602-GAA-GAAA

Variant names:

• chr16-81084602-G-GA
• rs202181338
• NM_004483.5:c.293-9dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_004483.5(GCSH):​c.293-9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00288 in 1,593,298 control chromosomes in the GnomAD database, including 85 homozygotes. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (45 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (40 hom.)
• Consequence: GCSH NM_004483.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.13
• 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: 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 -16 ACMG points.

• BP6: Variant 16-81084602-G-GA is Benign according to our data. Variant chr16-81084602-G-GA is described in ClinVar as Benign. ClinVar VariationId is 235601.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 = 0.0148 (2220/150192) while in subpopulation AFR AF = 0.0505 (2069/40966). AF 95% confidence interval is 0.0487. There are 45 homozygotes in GnomAd4. There are 1037 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 45 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.293-9dupT		intron	N/A	NP_004474.2
	GCSH	NR_033249.2		n.346-9dupT		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GCSH	ENST00000315467.9	TSL:1 MANE Select	c.293-9_293-8insT		intron	N/A	ENSP00000319531.3	P23434
	ENSG00000284512	ENST00000640345.1	TSL:5	c.293-9_293-8insT		intron	N/A	ENSP00000492798.1	A0A1W2PS29
	ENSG00000260643	ENST00000564536.2	TSL:5	c.293-9_293-8insT		intron	N/A	ENSP00000491651.1	A0A1W2PPQ1

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2218 AN: 150098 Hom.: 44 Cov.: 33

Gnomad AFR AF: 0.0506

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00530

Gnomad ASJ AF: 0.00751

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.000399

Gnomad OTH AF: 0.00824

GnomAD2 exomes AF: 0.00401 AC: 930 AN: 231840 AF XY: 0.00325

Gnomad AFR exome AF: 0.0504

Gnomad AMR exome AF: 0.00304

Gnomad ASJ exome AF: 0.00784

Gnomad EAS exome AF: 0.0000582

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000339

Gnomad OTH exome AF: 0.00191

GnomAD4 exome AF: 0.00164 AC: 2373 AN: 1443106 Hom.: 40 Cov.: 27 AF XY: 0.00150 AC XY: 1074 AN XY: 718358

African (AFR) AF: 0.0469 AC: 1540 AN: 32826

American (AMR) AF: 0.00344 AC: 151 AN: 43884

Ashkenazi Jewish (ASJ) AF: 0.00754 AC: 195 AN: 25856

East Asian (EAS) AF: 0.00 AC: 0 AN: 39478

South Asian (SAS) AF: 0.0000589 AC: 5 AN: 84872

European-Finnish (FIN) AF: 0.0000564 AC: 3 AN: 53154

Middle Eastern (MID) AF: 0.00227 AC: 13 AN: 5718

European-Non Finnish (NFE) AF: 0.000200 AC: 220 AN: 1097702

Other (OTH) AF: 0.00413 AC: 246 AN: 59616

GnomAD4 genome AF: 0.0148 AC: 2220 AN: 150192 Hom.: 45 Cov.: 33 AF XY: 0.0142 AC XY: 1037 AN XY: 73126

African (AFR) AF: 0.0505 AC: 2069 AN: 40966

American (AMR) AF: 0.00529 AC: 80 AN: 15114

Ashkenazi Jewish (ASJ) AF: 0.00751 AC: 26 AN: 3462

East Asian (EAS) AF: 0.00 AC: 0 AN: 5140

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9798

Middle Eastern (MID) AF: 0.00350 AC: 1 AN: 286

European-Non Finnish (NFE) AF: 0.000399 AC: 27 AN: 67648

Other (OTH) AF: 0.00816 AC: 17 AN: 2084

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.0176

Asia WGS AF: 0.00260 AC: 9 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Glycine encephalopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		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: rs202181338; hg19: chr16-81118207;