rs544404712

Variant names:

• chr3-81537067-T-G
• rs544404712
• NM_000158.4:c.1647A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM1 PM2

The NM_000158.4(GBE1):​c.1647A>C​(p.Leu549Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000193 in 1,554,992 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 0.644
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000158.4
• PM2: Very rare variant in population databases, with high coverage

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.1647A>C	p.Leu549Phe	missense	Exon 13 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.1647A>C	p.Leu549Phe	missense	Exon 13 of 16	ENSP00000410833.2
	GBE1	ENST00000489715.1	TSL:2	c.1524A>C	p.Leu508Phe	missense	Exon 13 of 16	ENSP00000419638.1
	GBE1	ENST00000484687.1	TSL:2	n.48A>C		non_coding_transcript_exon	Exon 2 of 3

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 152088 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 7.13e-7 AC: 1 AN: 1402786 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 695294

African (AFR) AF: 0.00 AC: 0 AN: 29996

American (AMR) AF: 0.00 AC: 0 AN: 34424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25016

East Asian (EAS) AF: 0.00 AC: 0 AN: 35124

South Asian (SAS) AF: 0.00 AC: 0 AN: 74022

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52712

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5646

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1087822

Other (OTH) AF: 0.0000172 AC: 1 AN: 58024

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152206 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74414

African (AFR) AF: 0.0000481 AC: 2 AN: 41576

American (AMR) AF: 0.00 AC: 0 AN: 15258

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67968

Other (OTH) AF: 0.00 AC: 0 AN: 2112

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Glycogen storage disease, type IV (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	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.76	D
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.29	D
MetaRNN	Uncertain	0.63	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Pathogenic	3.2	M
PhyloP100		0.64
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.9	D
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0030	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.53		Loss of glycosylation at K554 (P = 0.0669)
MVP		0.92
MPC		0.25
ClinPred		0.98	D
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.77
Mutation Taster		=7/93	disease causing

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: rs544404712; hg19: chr3-81586218;