rs397515344

Variant names:

• chr3-81648851-C-G
• rs397515344
• NM_000158.4:c.691+5G>C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PM2 PP3 PP5_Very_Strong

The NM_000158.4(GBE1):​c.691+5G>C variant causes a splice region, intron change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBE1 NM_000158.4 splice_region, intron
• Scores: Splicing: ADA: 0.9994
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 5.77
• Publications: 4 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: PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Laboratory for Molecular Medicine, Ambry Genetics, G2P, ClinGen
• adult polyglucosan body disease

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

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 3-81648851-C-G is Pathogenic according to our data. Variant chr3-81648851-C-G is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 2792.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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.691+5G>C		splice_region intron	N/A	NP_000149.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.691+5G>C		splice_region intron	N/A	ENSP00000410833.2
	GBE1	ENST00000489715.1	TSL:2	c.568+5G>C		splice_region intron	N/A	ENSP00000419638.1
	GBE1	ENST00000498468.1	TSL:3	n.219+5G>C		splice_region intron	N/A

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1332448 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 658994

African (AFR) AF: 0.00 AC: 0 AN: 27490

American (AMR) AF: 0.00 AC: 0 AN: 27752

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 22736

East Asian (EAS) AF: 0.00 AC: 0 AN: 35848

South Asian (SAS) AF: 0.00 AC: 0 AN: 66610

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49994

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4992

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1041946

Other (OTH) AF: 0.00 AC: 0 AN: 55080

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
3	-	-	Glycogen storage disease, type IV (3)
1	-	-	Glycogen storage disease due to glycogen branching enzyme deficiency, congenital neuromuscular form (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
BayesDel_noAF	Benign	-0.25
CADD	Benign	18
DANN	Benign	0.97
PhyloP100		5.8
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.91
SpliceAI score (max)		0.84		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.84		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs397515344; hg19: chr3-81698002;