3-81670803-A-G

Variant names:

• chr3-81670803-A-G
• rs151091415
• NM_000158.4:c.429+35T>C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000158.4(GBE1):​c.429+35T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00463 in 1,137,706 control chromosomes in the GnomAD database, including 24 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0048 (21 hom.)
• Consequence: GBE1 NM_000158.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.227
• Publications: 1 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: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 3-81670803-A-G is Benign according to our data. Variant chr3-81670803-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 255389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

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.429+35T>C		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.429+35T>C		intron	N/A	ENSP00000410833.2
	GBE1	ENST00000489715.1	TSL:2	c.306+35T>C		intron	N/A	ENSP00000419638.1
	GBE1	ENST00000477426.1	TSL:2	n.145+35T>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.00380 AC: 579 AN: 152196 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00223

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000622

Gnomad FIN AF: 0.00405

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00604

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00432 AC: 480 AN: 111002 AF XY: 0.00380

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00132

Gnomad ASJ exome AF: 0.00614

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00512

Gnomad NFE exome AF: 0.00565

Gnomad OTH exome AF: 0.00645

GnomAD4 exome AF: 0.00476 AC: 4688 AN: 985392 Hom.: 21 Cov.: 12 AF XY: 0.00470 AC XY: 2355 AN XY: 500586

African (AFR) AF: 0.00139 AC: 27 AN: 19402

American (AMR) AF: 0.00147 AC: 25 AN: 16956

Ashkenazi Jewish (ASJ) AF: 0.00640 AC: 134 AN: 20926

East Asian (EAS) AF: 0.00 AC: 0 AN: 31446

South Asian (SAS) AF: 0.00203 AC: 117 AN: 57670

European-Finnish (FIN) AF: 0.00550 AC: 274 AN: 49820

Middle Eastern (MID) AF: 0.00677 AC: 33 AN: 4876

European-Non Finnish (NFE) AF: 0.00522 AC: 3865 AN: 740556

Other (OTH) AF: 0.00487 AC: 213 AN: 43740

GnomAD4 genome AF: 0.00378 AC: 576 AN: 152314 Hom.: 3 Cov.: 32 AF XY: 0.00365 AC XY: 272 AN XY: 74474

African (AFR) AF: 0.00152 AC: 63 AN: 41570

American (AMR) AF: 0.00216 AC: 33 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4822

European-Finnish (FIN) AF: 0.00405 AC: 43 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00603 AC: 410 AN: 68024

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00557 Hom.: 2

Bravo AF: 0.00340

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.41
DANN	Benign	0.40
PhyloP100		-0.23
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: rs151091415; hg19: chr3-81719954;