rs2307130

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PVS1_ModerateBP6_Very_StrongBA1

The ENST00000370165.7(AGL):c.-8-2A>G variant causes a splice acceptor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.484 in 1,610,628 control chromosomes in the GnomAD database, including 191,964 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.42 ( 14097 hom., cov: 33)

Exomes 𝑓: 0.49 ( 177867 hom. )

Consequence

AGL
ENST00000370165.7 splice_acceptor

Scores

Splicing: ADA: 0.0001780

Clinical Significance

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

Conservation

PhyloP100: 0.357

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 -14 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.019352034 fraction of the gene. Cryptic splice site detected, with MaxEntScore 3.3, offset of -16, new splice context is: tcttttaattcttatgaaAGatt. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.

BP6

Variant 1-99851033-A-G is Benign according to our data. Variant chr1-99851033-A-G is described in ClinVar as [Benign]. Clinvar id is 195096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99851033-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.528 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3 linkuse as main transcript	c.-10A>G		5_prime_UTR_variant	2/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8 linkuse as main transcript	c.-10A>G		5_prime_UTR_variant	2/34	1	NM_000642.3	P1	P35573-1

Frequencies

GnomAD3 genomes

AF:

0.419

AC:

63647

AN:

151976

Hom.:

14073

Cov.:

show subpopulations

Gnomad AFR

AF:

0.263

Gnomad AMI

AF:

0.447

Gnomad AMR

AF:

0.434

Gnomad ASJ

AF:

0.395

Gnomad EAS

AF:

0.545

Gnomad SAS

AF:

0.543

Gnomad FIN

AF:

0.434

Gnomad MID

AF:

0.348

Gnomad NFE

AF:

0.490

Gnomad OTH

AF:

0.422

GnomAD3 exomes

AF:

0.469

AC:

117972

AN:

251340

Hom.:

28421

AF XY:

0.479

AC XY:

65025

AN XY:

135874

show subpopulations

Gnomad AFR exome

AF:

0.263

Gnomad AMR exome

AF:

0.439

Gnomad ASJ exome

AF:

0.390

Gnomad EAS exome

AF:

0.534

Gnomad SAS exome

AF:

0.537

Gnomad FIN exome

AF:

0.437

Gnomad NFE exome

AF:

0.492

Gnomad OTH exome

AF:

0.469

GnomAD4 exome

AF:

0.491

AC:

715475

AN:

1458534

Hom.:

177867

Cov.:

AF XY:

0.493

AC XY:

357476

AN XY:

725786

show subpopulations

Gnomad4 AFR exome

AF:

0.258

Gnomad4 AMR exome

AF:

0.435

Gnomad4 ASJ exome

AF:

0.398

Gnomad4 EAS exome

AF:

0.545

Gnomad4 SAS exome

AF:

0.538

Gnomad4 FIN exome

AF:

0.443

Gnomad4 NFE exome

AF:

0.500

Gnomad4 OTH exome

AF:

0.472

GnomAD4 genome

AF:

0.419

AC:

63701

AN:

152094

Hom.:

14097

Cov.:

AF XY:

0.420

AC XY:

31205

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.263

Gnomad4 AMR

AF:

0.435

Gnomad4 ASJ

AF:

0.395

Gnomad4 EAS

AF:

0.545

Gnomad4 SAS

AF:

0.545

Gnomad4 FIN

AF:

0.434

Gnomad4 NFE

AF:

0.490

Gnomad4 OTH

AF:

0.431

Alfa

AF:

0.471

Hom.:

33647

Bravo

AF:

0.413

Asia WGS

AF:

0.530

AC:

1845

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Glycogen storage disease type III

Benign:4

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. -
Benign, criteria provided, single submitter	clinical testing	Phosphorus, Inc.	Aug 01, 2017	- -
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	- -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 02, 2015	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	Eurofins Ntd Llc (ga)	Sep 24, 2014	- -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 22, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.73

CADD

Benign

DANN

Benign

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00018

dbscSNV1_RF

Benign

0.0

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