chr3-81705468-CT-C

Variant names:

• chr3-81705468-CT-C
• rs1057517315
• NM_000158.4:c.288delA

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_000158.4(GBE1):​c.288delA​(p.Gly97GlufsTer46) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000277 in 1,443,200 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. E96E) has been classified as Uncertain significance. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000028 (0 hom.)
• Consequence: GBE1 NM_000158.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 2.23
• Publications: 2 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 18 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
• PP5: Variant 3-81705468-CT-C is Pathogenic according to our data. Variant chr3-81705468-CT-C is described in ClinVar as Pathogenic. ClinVar VariationId is 371491.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.288delA	p.Gly97GlufsTer46	frameshift	Exon 2 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.288delA	p.Gly97GlufsTer46	frameshift	Exon 2 of 16	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.288delA	p.Gly97GlufsTer46	frameshift	Exon 2 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.288delA	p.Gly97GlufsTer46	frameshift	Exon 2 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000277 AC: 4 AN: 1443200 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 716266

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

African (AFR) AF: 0.00 AC: 0 AN: 32832

American (AMR) AF: 0.00 AC: 0 AN: 41760

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25772

East Asian (EAS) AF: 0.0000513 AC: 2 AN: 38994

South Asian (SAS) AF: 0.00 AC: 0 AN: 81258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5732

European-Non Finnish (NFE) AF: 9.06e-7 AC: 1 AN: 1104128

Other (OTH) AF: 0.0000167 AC: 1 AN: 59752

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0404278), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Glycogen storage disease, type IV (2)
1	-	-	Glycogen storage disease, type IV;C1849722:Adult polyglucosan body disease (1)
1	-	-	Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic (1)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.2
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1057517315; hg19: chr3-81754619;