3-81490255-G-T

Position:

• chr3-81490255-G-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.*152C>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 0.0417 in 652,126 control chromosomes in the GnomAD database, including 992 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (445 hom., cov: 31)
  • Exomes 𝑓: 0.036 (547 hom.)
• Consequence: GBE1 NM_000158.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.954

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=-0.87).
• BP6: Variant 3-81490255-G-T is Benign according to our data. Variant chr3-81490255-G-T is described in ClinVar as [Benign]. Clinvar id is 346782.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.122 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GBE1	NM_000158.4	c.*152C>A		3_prime_UTR_variant	16/16	ENST00000429644.7	NP_000149.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GBE1	ENST00000429644	c.*152C>A		3_prime_UTR_variant	16/16	1	NM_000158.4	ENSP00000410833.2
GBE1	ENST00000489715	c.*152C>A		3_prime_UTR_variant	16/16	2		ENSP00000419638.1

Frequencies

GnomAD3 genomes AF: 0.0600 AC: 9123 AN: 152082 Hom.: 443 Cov.: 31

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0675

Gnomad ASJ AF: 0.0230

Gnomad EAS AF: 0.0627

Gnomad SAS AF: 0.0408

Gnomad FIN AF: 0.0308

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.0269

Gnomad OTH AF: 0.0561

GnomAD4 exome AF: 0.0361 AC: 18037 AN: 499926 Hom.: 547 Cov.: 6 AF XY: 0.0356 AC XY: 9526 AN XY: 267732

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.0570

Gnomad4 ASJ exome AF: 0.0227

Gnomad4 EAS exome AF: 0.0868

Gnomad4 SAS exome AF: 0.0459

Gnomad4 FIN exome AF: 0.0315

Gnomad4 NFE exome AF: 0.0253

Gnomad4 OTH exome AF: 0.0379

GnomAD4 genome AF: 0.0600 AC: 9131 AN: 152200 Hom.: 445 Cov.: 31 AF XY: 0.0606 AC XY: 4508 AN XY: 74414

Gnomad4 AFR AF: 0.124

Gnomad4 AMR AF: 0.0673

Gnomad4 ASJ AF: 0.0230

Gnomad4 EAS AF: 0.0624

Gnomad4 SAS AF: 0.0408

Gnomad4 FIN AF: 0.0308

Gnomad4 NFE AF: 0.0269

Gnomad4 OTH AF: 0.0565

Alfa AF: 0.0322 Hom.: 128

Bravo AF: 0.0641

Asia WGS AF: 0.0600 AC: 211 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 23, 2018	- -

Glycogen storage disease, type IV Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	1.8
DANN	Benign	0.23

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: rs9820089; hg19: chr3-81539406;