3-81578024-T-C

Variant names:

• chr3-81578024-T-C
• rs2228389
• NM_000158.4:c.1519A>G

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 2P and 20B. PM1 BP4_Strong BP6_Very_Strong BA1

The NM_000158.4(GBE1):​c.1519A>G​(p.Thr507Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,609,436 control chromosomes in the GnomAD database, including 1,845 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T507T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.065 (541 hom., cov: 32)
  • Exomes 𝑓: 0.033 (1304 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.0520
• Publications: 16 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, G2P, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, Genomics England PanelApp, Ambry Genetics
• adult polyglucosan body disease

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

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000158.4
• BP4: Computational evidence support a benign effect (MetaRNN=0.001793772).
• BP6: Variant 3-81578024-T-C is Benign according to our data. Variant chr3-81578024-T-C is described in ClinVar as Benign. ClinVar VariationId is 255383.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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.1519A>G	p.Thr507Ala	missense	Exon 12 of 16	NP_000149.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.1519A>G	p.Thr507Ala	missense	Exon 12 of 16	ENSP00000410833.2
	GBE1	ENST00000895874.1		c.1513A>G	p.Thr505Ala	missense	Exon 12 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.1513A>G	p.Thr505Ala	missense	Exon 12 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes AF: 0.0651 AC: 9872 AN: 151738 Hom.: 539 Cov.: 32

Gnomad AFR AF: 0.142

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0704

Gnomad ASJ AF: 0.0158

Gnomad EAS AF: 0.0630

Gnomad SAS AF: 0.0422

Gnomad FIN AF: 0.0313

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0270

Gnomad OTH AF: 0.0618

GnomAD2 exomes AF: 0.0420 AC: 10239 AN: 243764 AF XY: 0.0400

Gnomad AFR exome AF: 0.138

Gnomad AMR exome AF: 0.0607

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.0502

Gnomad FIN exome AF: 0.0314

Gnomad NFE exome AF: 0.0248

Gnomad OTH exome AF: 0.0367

GnomAD4 exome AF: 0.0334 AC: 48730 AN: 1457580 Hom.: 1304 Cov.: 31 AF XY: 0.0335 AC XY: 24277 AN XY: 724906

African (AFR) AF: 0.144 AC: 4772 AN: 33206

American (AMR) AF: 0.0615 AC: 2706 AN: 44006

Ashkenazi Jewish (ASJ) AF: 0.0175 AC: 455 AN: 26072

East Asian (EAS) AF: 0.0815 AC: 3216 AN: 39476

South Asian (SAS) AF: 0.0486 AC: 4149 AN: 85340

European-Finnish (FIN) AF: 0.0319 AC: 1703 AN: 53336

Middle Eastern (MID) AF: 0.0686 AC: 395 AN: 5762

European-Non Finnish (NFE) AF: 0.0262 AC: 29045 AN: 1110134

Other (OTH) AF: 0.0380 AC: 2289 AN: 60248

GnomAD4 genome AF: 0.0650 AC: 9877 AN: 151856 Hom.: 541 Cov.: 32 AF XY: 0.0653 AC XY: 4846 AN XY: 74180

African (AFR) AF: 0.142 AC: 5873 AN: 41380

American (AMR) AF: 0.0702 AC: 1068 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.0158 AC: 55 AN: 3472

East Asian (EAS) AF: 0.0628 AC: 324 AN: 5160

South Asian (SAS) AF: 0.0423 AC: 203 AN: 4804

European-Finnish (FIN) AF: 0.0313 AC: 329 AN: 10524

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.0270 AC: 1836 AN: 67984

Other (OTH) AF: 0.0621 AC: 131 AN: 2108

Alfa AF: 0.0394 Hom.: 758

Bravo AF: 0.0700

TwinsUK AF: 0.0254 AC: 94

ALSPAC AF: 0.0285 AC: 110

ESP6500AA AF: 0.120 AC: 467

ESP6500EA AF: 0.0229 AC: 190

ExAC AF: 0.0431 AC: 5210

Asia WGS AF: 0.0600 AC: 211 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	2	Glycogen storage disease, type IV (2)
-	-	2	not provided (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
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	-0.57	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	10
DANN	Benign	0.90
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.99
FATHMM_MKL	Benign	0.089	N
LIST_S2	Benign	0.72	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Pathogenic	3.1	M
PhyloP100		0.052
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.26
Sift	Benign	0.30	T
Sift4G	Benign	0.70	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.030
ClinPred		0.017	T
GERP RS		-5.5
Varity_R		0.13
gMVP		0.45
Mutation Taster		=100/0	polymorphism (auto)

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: rs2228389; hg19: chr3-81627175; COSMIC: COSV107525203;