chr3-81670925-G-C

Variant names:

• chr3-81670925-G-C
• rs13320194
• NM_000158.4:c.342C>G

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_000158.4(GBE1):​c.342C>G​(p.Tyr114*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000707 in 1,414,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Y114Y) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GBE1 NM_000158.4 stop_gained
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.736
• 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: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• adult polyglucosan body disease

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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.342C>G	p.Tyr114*	stop_gained	Exon 3 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.342C>G	p.Tyr114*	stop_gained	Exon 3 of 16	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.342C>G	p.Tyr114*	stop_gained	Exon 3 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.342C>G	p.Tyr114*	stop_gained	Exon 3 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.07e-7 AC: 1 AN: 1414726 Hom.: 0 Cov.: 28 AF XY: 0.00000143 AC XY: 1 AN XY: 701278

African (AFR) AF: 0.00 AC: 0 AN: 30908

American (AMR) AF: 0.00 AC: 0 AN: 37238

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25332

East Asian (EAS) AF: 0.0000268 AC: 1 AN: 37338

South Asian (SAS) AF: 0.00 AC: 0 AN: 77462

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52298

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5704

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1089880

Other (OTH) AF: 0.00 AC: 0 AN: 58566

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.56	D
BayesDel_noAF	Pathogenic	0.57
CADD	Pathogenic	33
DANN	Uncertain	1.0
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Benign	0.62	D
PhyloP100		0.74
Vest4		0.71
GERP RS		4.3
Mutation Taster		=1/199	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs13320194; hg19: chr3-81720076;