rs147165298

Positions:

chr1-99892551-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000642.3(AGL):c.3203A>G(p.Tyr1068Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000314 in 1,613,624 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. Y1068Y) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0017 ( 3 hom., cov: 33)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: 2.57

Variant links:

Genes affected

AGL (HGNC:321): (amylo-alpha-1, 6-glucosidase, 4-alpha-glucanotransferase) This gene encodes the glycogen debrancher enzyme which is involved in glycogen degradation. This enzyme has two independent catalytic activities which occur at different sites on the protein: a 4-alpha-glucotransferase activity and a amylo-1,6-glucosidase activity. Mutations in this gene are associated with glycogen storage disease although a wide range of enzymatic and clinical variability occurs which may be due to tissue-specific alternative splicing. Alternatively spliced transcripts encoding different isoforms have been described. [provided by RefSeq, Jul 2008]

AGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0116404).

BP6

Variant 1-99892551-A-G is Benign according to our data. Variant chr1-99892551-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 281333.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00175 (266/152256) while in subpopulation AFR AF= 0.00599 (249/41560). AF 95% confidence interval is 0.00538. There are 3 homozygotes in gnomad4. There are 132 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3 linkuse as main transcript	c.3203A>G	p.Tyr1068Cys	missense_variant	24/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8 linkuse as main transcript	c.3203A>G	p.Tyr1068Cys	missense_variant	24/34	1	NM_000642.3	P1	P35573-1

Frequencies

GnomAD3 genomes

AF:

0.00175

AC:

266

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00601

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000721

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:

0.0000147

Gnomad OTH

AF:

0.00239

GnomAD3 exomes

AF:

0.000462

AC:

116

AN:

251198

Hom.:

AF XY:

0.000405

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.00585

Gnomad AMR exome

AF:

0.000290

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.000326

GnomAD4 exome

AF:

0.000164

AC:

240

AN:

1461368

Hom.:

Cov.:

AF XY:

0.000153

AC XY:

111

AN XY:

726998

show subpopulations

Gnomad4 AFR exome

AF:

0.00547

Gnomad4 AMR exome

AF:

0.000425

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000177

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000450

Gnomad4 OTH exome

AF:

0.000364

GnomAD4 genome

AF:

0.00175

AC:

266

AN:

152256

Hom.:

Cov.:

AF XY:

0.00177

AC XY:

132

AN XY:

74454

show subpopulations

Gnomad4 AFR

AF:

0.00599

Gnomad4 AMR

AF:

0.000720

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00237

Alfa

AF:

0.000349

Hom.:

Bravo

AF:

0.00182

ESP6500AA

AF:

0.00635

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000684

AC:

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 02, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	AGL: BP4, BS2 -

Glycogen storage disease type III

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 29, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -

not specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Jun 10, 2015

- -

AGL-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Aug 15, 2019

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.37

BayesDel_noAF

Benign

-0.30

CADD

Benign

DANN

Benign

0.42

DEOGEN2

Benign

0.13

T;T;T;T;.

Eigen

Benign

-0.56

Eigen_PC

Benign

-0.54

FATHMM_MKL

Uncertain

0.76

LIST_S2

Benign

0.81

T;.;.;.;T

M_CAP

Benign

0.022

MetaRNN

Benign

0.012

T;T;T;T;T

MetaSVM

Benign

-0.96

MutationAssessor

Uncertain

2.2

M;M;M;M;.

MutationTaster

Benign

0.88

D;D;D;D;D;D;D

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.37

N;N;N;N;N

REVEL

Benign

0.10

Sift

Benign

0.18

T;T;T;T;T

Sift4G

Benign

0.17

T;T;T;T;T

Polyphen

0.0

B;B;B;B;B

Vest4

0.27

MVP

0.77

MPC

0.048

ClinPred

0.011

GERP RS

2.8

Varity_R

0.046

gMVP

0.74

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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