rs193074572

Variant names:

• chr3-81499145-C-T
• rs193074572
• NM_000158.4:c.2017G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000158.4(GBE1):​c.2017G>A​(p.Ala673Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00781 in 1,609,962 control chromosomes in the GnomAD database, including 64 homozygotes. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0081 (58 hom.)
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: -1.20
• Publications: 12 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: Ambry Genetics, Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• adult polyglucosan body disease

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0044651926).
• BP6: Variant 3-81499145-C-T is Benign according to our data. Variant chr3-81499145-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 235560.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00514 (782/152188) while in subpopulation NFE AF = 0.00836 (568/67980). AF 95% confidence interval is 0.00779. There are 6 homozygotes in GnomAd4. There are 359 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 6 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	NM_000158.4	MANE Select	c.2017G>A	p.Ala673Thr	missense	Exon 15 of 16	NP_000149.4	Q04446

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GBE1	ENST00000429644.7	TSL:1 MANE Select	c.2017G>A	p.Ala673Thr	missense	Exon 15 of 16	ENSP00000410833.2	Q04446
	GBE1	ENST00000895874.1		c.2011G>A	p.Ala671Thr	missense	Exon 15 of 16	ENSP00000565933.1
	GBE1	ENST00000942742.1		c.2011G>A	p.Ala671Thr	missense	Exon 15 of 16	ENSP00000612801.1

Frequencies

GnomAD3 genomes AF: 0.00514 AC: 782 AN: 152070 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00130

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00655

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00249

Gnomad FIN AF: 0.00274

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00835

Gnomad OTH AF: 0.00526

GnomAD2 exomes AF: 0.00502 AC: 1235 AN: 246198 AF XY: 0.00521

Gnomad AFR exome AF: 0.00183

Gnomad AMR exome AF: 0.00252

Gnomad ASJ exome AF: 0.00140

Gnomad EAS exome AF: 0.0000563

Gnomad FIN exome AF: 0.00285

Gnomad NFE exome AF: 0.00843

Gnomad OTH exome AF: 0.00486

GnomAD4 exome AF: 0.00809 AC: 11799 AN: 1457774 Hom.: 58 Cov.: 29 AF XY: 0.00798 AC XY: 5790 AN XY: 725116

African (AFR) AF: 0.00108 AC: 36 AN: 33402

American (AMR) AF: 0.00272 AC: 121 AN: 44462

Ashkenazi Jewish (ASJ) AF: 0.00138 AC: 36 AN: 26058

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39596

South Asian (SAS) AF: 0.00288 AC: 247 AN: 85696

European-Finnish (FIN) AF: 0.00328 AC: 175 AN: 53310

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5764

European-Non Finnish (NFE) AF: 0.00975 AC: 10813 AN: 1109236

Other (OTH) AF: 0.00609 AC: 367 AN: 60250

GnomAD4 genome AF: 0.00514 AC: 782 AN: 152188 Hom.: 6 Cov.: 32 AF XY: 0.00482 AC XY: 359 AN XY: 74412

African (AFR) AF: 0.00130 AC: 54 AN: 41538

American (AMR) AF: 0.00655 AC: 100 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5190

South Asian (SAS) AF: 0.00249 AC: 12 AN: 4818

European-Finnish (FIN) AF: 0.00274 AC: 29 AN: 10596

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

European-Non Finnish (NFE) AF: 0.00836 AC: 568 AN: 67980

Other (OTH) AF: 0.00520 AC: 11 AN: 2114

Alfa AF: 0.00693 Hom.: 6

Bravo AF: 0.00539

TwinsUK AF: 0.00917 AC: 34

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00164 AC: 6

ESP6500EA AF: 0.00660 AC: 54

ExAC AF: 0.00496 AC: 599

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	7	not provided (7)
-	-	2	not specified (2)
-	-	1	Adult polyglucosan body disease (1)
-	-	1	Glycogen storage disease, type IV (1)
-	-	1	Glycogen storage disease, type IV;C1849722: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	0.073
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	15
DANN	Benign	0.96
DEOGEN2	Benign	0.27	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.038	N
LIST_S2	Benign	0.65	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.0045	T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	0.72	N
PhyloP100		-1.2
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.31	N
REVEL	Benign	0.17
Sift	Benign	0.14	T
Sift4G	Benign	0.43	T
Polyphen		0.040	B
Vest4		0.13
MVP		0.58
MPC		0.030
ClinPred		0.015	T
GERP RS		-6.4
Varity_R		0.31
gMVP		0.26
Mutation Taster		=92/8	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: rs193074572; hg19: chr3-81548296; COSMIC: COSV107525264;