rs372821643

Variant names:

• chr3-81578022-A-G
• rs372821643
• NM_000158.4:c.1521T>C

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000158.4(GBE1):​c.1521T>C​(p.Thr507Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00174 in 1,610,794 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0012 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0018 (0 hom.)
• Consequence: GBE1 NM_000158.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:7
• Conservation: PhyloP100: -0.313
• 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 3-81578022-A-G is Benign according to our data. Variant chr3-81578022-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211070.
• BP7: Synonymous conserved (PhyloP=-0.313 with no splicing effect.

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.1521T>C	p.Thr507Thr	synonymous	Exon 12 of 16	NP_000149.4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1521T>C	p.Thr507Thr	synonymous	Exon 12 of 16	ENSP00000410833.2
	GBE1	ENST00000489715.1	TSL:2	c.1398T>C	p.Thr466Thr	synonymous	Exon 12 of 16	ENSP00000419638.1
	GBE1	ENST00000484687.1	TSL:2	n.-79T>C		upstream_gene	N/A

Frequencies

GnomAD3 genomes AF: 0.00125 AC: 190 AN: 152146 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.00115 AC: 281 AN: 244664 AF XY: 0.00125

Gnomad AFR exome AF: 0.000132

Gnomad AMR exome AF: 0.0000602

Gnomad ASJ exome AF: 0.000200

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000466

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.000680

GnomAD4 exome AF: 0.00179 AC: 2605 AN: 1458530 Hom.: 0 Cov.: 31 AF XY: 0.00180 AC XY: 1309 AN XY: 725376

African (AFR) AF: 0.000270 AC: 9 AN: 33318

American (AMR) AF: 0.000181 AC: 8 AN: 44178

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39526

South Asian (SAS) AF: 0.00113 AC: 97 AN: 85482

European-Finnish (FIN) AF: 0.000450 AC: 24 AN: 53348

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5762

European-Non Finnish (NFE) AF: 0.00215 AC: 2388 AN: 1110532

Other (OTH) AF: 0.00128 AC: 77 AN: 60290

GnomAD4 genome AF: 0.00125 AC: 190 AN: 152264 Hom.: 1 Cov.: 32 AF XY: 0.00125 AC XY: 93 AN XY: 74446

African (AFR) AF: 0.000265 AC: 11 AN: 41554

American (AMR) AF: 0.000458 AC: 7 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00207 AC: 10 AN: 4826

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10618

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

European-Non Finnish (NFE) AF: 0.00229 AC: 156 AN: 68014

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.00164 Hom.: 0

Bravo AF: 0.00111

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	Glycogen storage disease, type IV (3)
-	-	3	not provided (3)
-	1	1	not specified (2)
-	1	-	Adult polyglucosan body disease (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	-0.80
CADD	Benign	8.4
DANN	Benign	0.39
PhyloP100		-0.31
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs372821643; hg19: chr3-81627173;