3-81490231-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000158.4(GBE1):c.*176G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 587,666 control chromosomes in the GnomAD database, including 54,696 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (11426 hom., cov: 32)
  • Exomes 𝑓: 0.43 (43270 hom.)
• Consequence: GBE1 NM_000158.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0750

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-81490231-C-T is Benign according to our data. Variant chr3-81490231-C-T is described in ClinVar as [Benign]. Clinvar id is 346781.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.532 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.*176G>A		3_prime_UTR_variant	16/16	ENST00000429644.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.*176G>A		3_prime_UTR_variant	16/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.*176G>A		3_prime_UTR_variant	16/16	2

Frequencies

GnomAD3 genomes AF: 0.365 AC: 55393 AN: 151922 Hom.: 11420 Cov.: 32

Gnomad AFR AF: 0.185

Gnomad AMI AF: 0.603

Gnomad AMR AF: 0.419

Gnomad ASJ AF: 0.605

Gnomad EAS AF: 0.0852

Gnomad SAS AF: 0.550

Gnomad FIN AF: 0.395

Gnomad MID AF: 0.481

Gnomad NFE AF: 0.448

Gnomad OTH AF: 0.409

GnomAD4 exome AF: 0.432 AC: 187997 AN: 435624 Hom.: 43270 Cov.: 4 AF XY: 0.441 AC XY: 102264 AN XY: 231764

Gnomad4 AFR exome AF: 0.189

Gnomad4 AMR exome AF: 0.417

Gnomad4 ASJ exome AF: 0.593

Gnomad4 EAS exome AF: 0.140

Gnomad4 SAS exome AF: 0.570

Gnomad4 FIN exome AF: 0.380

Gnomad4 NFE exome AF: 0.451

Gnomad4 OTH exome AF: 0.425

GnomAD4 genome AF: 0.364 AC: 55411 AN: 152042 Hom.: 11426 Cov.: 32 AF XY: 0.365 AC XY: 27108 AN XY: 74302

Gnomad4 AFR AF: 0.185

Gnomad4 AMR AF: 0.419

Gnomad4 ASJ AF: 0.605

Gnomad4 EAS AF: 0.0852

Gnomad4 SAS AF: 0.549

Gnomad4 FIN AF: 0.395

Gnomad4 NFE AF: 0.448

Gnomad4 OTH AF: 0.406

Alfa AF: 0.382 Hom.: 2122

Bravo AF: 0.352

Asia WGS AF: 0.304 AC: 1057 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Adult polyglucosan body disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 26, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
Cadd	Benign	0.97
Dann	Benign	0.52

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

Publications

LitVar

Other links and lift over

dbSNP: rs846; hg19: chr3-81539382; COSMIC: COSV70103732;