rs370246900

Variant names:

• chr3-81536933-T-C
• rs370246900
• NM_000158.4:c.1781A>G
• GBE1 p.Tyr594Cys

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_000158.4(GBE1):​c.1781A>G​(p.Tyr594Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000105 in 1,432,354 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. Y594Y) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.0240
• Publications: 0 publications found

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

GBE1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to glycogen branching enzyme deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, Genomics England PanelApp
• adult polyglucosan body disease

  Inheritance: AR Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.16131967).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000158.4. 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
	GBE1	NM_000158.4	MANE Select	c.1781A>G	p.Tyr594Cys	missense	Exon 13 of 16	NP_000149.4	Q04446

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1781A>G	p.Tyr594Cys	missense	Exon 13 of 16	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.1775A>G	p.Tyr592Cys	missense	Exon 13 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.1775A>G	p.Tyr592Cys	missense	Exon 13 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000227 AC: 5 AN: 220138 AF XY: 0.0000333

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000490

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000105 AC: 15 AN: 1432354 Hom.: 0 Cov.: 30 AF XY: 0.0000155 AC XY: 11 AN XY: 711674

African (AFR) AF: 0.00 AC: 0 AN: 31378

American (AMR) AF: 0.00 AC: 0 AN: 40178

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25582

East Asian (EAS) AF: 0.00 AC: 0 AN: 37142

South Asian (SAS) AF: 0.0000124 AC: 1 AN: 80352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53182

Middle Eastern (MID) AF: 0.000703 AC: 4 AN: 5688

European-Non Finnish (NFE) AF: 0.00000909 AC: 10 AN: 1099610

Other (OTH) AF: 0.00 AC: 0 AN: 59242

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000450 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease, type IV (1)
-	1	-	Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	10
DANN	Benign	0.92
DEOGEN2	Uncertain	0.68	D
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.49
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		0.024
PrimateAI	Benign	0.33	T
PROVEAN	Pathogenic	-7.2	D
REVEL	Benign	0.29
Sift	Benign	0.079	T
Sift4G	Benign	0.11	T
Varity_R		0.43
gMVP		0.67
Mutation Taster		=60/40	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs370246900;

hg19: chr3-81586084;