3-81594016-T-C

Position:

chr3-81594016-T-C

Variant summary

Our verdict is Benign. Variant got -18 ACMG points: 2P and 20B. PM1BP4_StrongBP6_Very_StrongBA1

The NM_000158.4(GBE1):c.1000A>G(p.Ile334Val) variant causes a missense change. The variant allele was found at a frequency of 0.972 in 1,505,534 control chromosomes in the GnomAD database, including 711,835 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.98 ( 72929 hom., cov: 31)

Exomes 𝑓: 0.97 ( 638906 hom. )

Consequence

GBE1
NM_000158.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 5.82

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -18 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000158.4

BP4

Computational evidence support a benign effect (MetaRNN=7.2837616E-7).

BP6

Variant 3-81594016-T-C is Benign according to our data. Variant chr3-81594016-T-C is described in ClinVar as [Benign]. Clinvar id is 1168034.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-81594016-T-C is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.988 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4 linkuse as main transcript	c.1000A>G	p.Ile334Val	missense_variant	8/16	ENST00000429644.7
GBE1	XR_007095662.1 linkuse as main transcript	n.1128A>G		non_coding_transcript_exon_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7 linkuse as main transcript	c.1000A>G	p.Ile334Val	missense_variant	8/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1 linkuse as main transcript	c.877A>G	p.Ile293Val	missense_variant	8/16	2

Frequencies

GnomAD3 genomes

AF:

0.979

AC:

148874

AN:

152116

Hom.:

72872

Cov.:

show subpopulations

Gnomad AFR

AF:

0.996

Gnomad AMI

AF:

0.996

Gnomad AMR

AF:

0.988

Gnomad ASJ

AF:

0.986

Gnomad EAS

AF:

0.999

Gnomad SAS

AF:

0.963

Gnomad FIN

AF:

0.958

Gnomad MID

AF:

0.968

Gnomad NFE

AF:

0.969

Gnomad OTH

AF:

0.981

GnomAD3 exomes

AF:

0.976

AC:

178058

AN:

182518

Hom.:

86882

AF XY:

0.974

AC XY:

94272

AN XY:

96810

show subpopulations

Gnomad AFR exome

AF:

0.996

Gnomad AMR exome

AF:

0.990

Gnomad ASJ exome

AF:

0.988

Gnomad EAS exome

AF:

1.00

Gnomad SAS exome

AF:

0.964

Gnomad FIN exome

AF:

0.959

Gnomad NFE exome

AF:

0.969

Gnomad OTH exome

AF:

0.978

GnomAD4 exome

AF:

0.972

AC:

1314913

AN:

1353300

Hom.:

638906

Cov.:

AF XY:

0.971

AC XY:

653309

AN XY:

672632

show subpopulations

Gnomad4 AFR exome

AF:

0.997

Gnomad4 AMR exome

AF:

0.990

Gnomad4 ASJ exome

AF:

0.985

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.964

Gnomad4 FIN exome

AF:

0.958

Gnomad4 NFE exome

AF:

0.970

Gnomad4 OTH exome

AF:

0.974

GnomAD4 genome

AF:

0.979

AC:

148990

AN:

152234

Hom.:

72929

Cov.:

AF XY:

0.978

AC XY:

72803

AN XY:

74416

show subpopulations

Gnomad4 AFR

AF:

0.996

Gnomad4 AMR

AF:

0.988

Gnomad4 ASJ

AF:

0.986

Gnomad4 EAS

AF:

0.999

Gnomad4 SAS

AF:

0.962

Gnomad4 FIN

AF:

0.958

Gnomad4 NFE

AF:

0.969

Gnomad4 OTH

AF:

0.981

Alfa

AF:

0.973

Hom.:

91996

Bravo

AF:

0.983

TwinsUK

AF:

0.972

AC:

3606

ALSPAC

AF:

0.972

AC:

3747

ESP6500AA

AF:

0.996

AC:

3602

ESP6500EA

AF:

0.972

AC:

7924

ExAC

AF:

0.969

AC:

112433

Asia WGS

AF:

0.984

AC:

3418

AN:

3474

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Glycogen storage disease, type IV

Benign:3

Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Aug 28, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -

Adult polyglucosan body disease

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 10, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Pars Genome Lab	Jun 15, 2021	- -

Glycogen storage disease, type IV;C1856301:Glycogen storage disease IV, classic hepatic

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.051

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.37

CADD

Benign

DANN

Benign

0.49

DEOGEN2

Benign

0.12

T;T

Eigen

Benign

-0.88

Eigen_PC

Benign

-0.52

FATHMM_MKL

Benign

0.21

LIST_S2

Benign

0.57

T;T

MetaRNN

Benign

7.3e-7

T;T

MetaSVM

Benign

-0.92

MutationAssessor

Benign

-3.1

N;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Uncertain

0.56

PROVEAN

Benign

0.95

N;N

REVEL

Benign

0.28

Sift

Benign

1.0

T;T

Sift4G

Benign

1.0

T;T

Polyphen

0.0

B;B

Vest4

0.062

MPC

0.028

ClinPred

0.012

GERP RS

5.7

Varity_R

0.033

gMVP

0.58

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over