1-99875226-G-T

Position:

chr1-99875226-G-T

Variant summary

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

The NM_000642.3(AGL):c.1155G>T(p.Lys385Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,614,052 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 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. K385K) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.013 ( 24 hom., cov: 33)

Exomes 𝑓: 0.013 ( 156 hom. )

Consequence

AGL
NM_000642.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13

Conservation

PhyloP100: 0.784

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=0.0034376383).

BP6

Variant 1-99875226-G-T is Benign according to our data. Variant chr1-99875226-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99875226-G-T is described in Lovd as [Benign]. Variant chr1-99875226-G-T is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1925/152328) while in subpopulation NFE AF= 0.0152 (1034/68022). AF 95% confidence interval is 0.0144. There are 24 homozygotes in gnomad4. There are 979 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
AGL	NM_000642.3 link	c.1155G>T	p.Lys385Asn	missense_variant	9/34	ENST00000361915.8	NP_000633.2	P35573-1A0A0S2A4E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 link	c.1155G>T	p.Lys385Asn	missense_variant	9/34	1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.0127

AC:

1927

AN:

152210

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00239

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0143

Gnomad ASJ

AF:

0.0294

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00435

Gnomad FIN

AF:

0.0359

Gnomad MID

AF:

0.0886

Gnomad NFE

AF:

0.0152

Gnomad OTH

AF:

0.0211

GnomAD3 exomes

AF:

0.0135

AC:

3375

AN:

250696

Hom.:

AF XY:

0.0135

AC XY:

1830

AN XY:

135732

show subpopulations

Gnomad AFR exome

AF:

0.00176

Gnomad AMR exome

AF:

0.00645

Gnomad ASJ exome

AF:

0.0286

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.00363

Gnomad FIN exome

AF:

0.0340

Gnomad NFE exome

AF:

0.0165

Gnomad OTH exome

AF:

0.0192

GnomAD4 exome

AF:

0.0126

AC:

18416

AN:

1461724

Hom.:

156

Cov.:

AF XY:

0.0127

AC XY:

9219

AN XY:

727156

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.00736

Gnomad4 ASJ exome

AF:

0.0290

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00422

Gnomad4 FIN exome

AF:

0.0345

Gnomad4 NFE exome

AF:

0.0125

Gnomad4 OTH exome

AF:

0.0142

GnomAD4 genome

AF:

0.0126

AC:

1925

AN:

152328

Hom.:

Cov.:

AF XY:

0.0131

AC XY:

979

AN XY:

74492

show subpopulations

Gnomad4 AFR

AF:

0.00238

Gnomad4 AMR

AF:

0.0142

Gnomad4 ASJ

AF:

0.0294

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00435

Gnomad4 FIN

AF:

0.0359

Gnomad4 NFE

AF:

0.0152

Gnomad4 OTH

AF:

0.0208

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0102

TwinsUK

AF:

0.00971

AC:

ALSPAC

AF:

0.0135

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0155

AC:

133

ExAC

AF:

0.0140

AC:

1698

Asia WGS

AF:

0.00433

AC:

AN:

3478

EpiCase

AF:

0.0167

EpiControl

AF:

0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:6

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 02, 2025	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
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. -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:5

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2024	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2024	AGL: BP4, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.45

CADD

Benign

DANN

Benign

0.94

DEOGEN2

Benign

0.057

T;T;T;T;.

Eigen

Benign

-0.76

Eigen_PC

Benign

-0.83

FATHMM_MKL

Benign

0.43

LIST_S2

Benign

0.83

T;.;.;.;T

MetaRNN

Benign

0.0034

T;T;T;T;T

MetaSVM

Benign

-0.66

MutationAssessor

Benign

1.7

L;L;L;L;.

PrimateAI

Benign

0.40

PROVEAN

Benign

-1.2

N;N;N;N;N

REVEL

Benign

0.25

Sift

Benign

0.084

T;T;T;T;T

Sift4G

Benign

0.12

T;T;T;T;T

Polyphen

0.18

B;B;B;B;B

Vest4

0.14

MutPred

0.30

Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);.;

MPC

0.060

ClinPred

0.011

GERP RS

-0.33

Varity_R

0.11

gMVP

0.58

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.060

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