rs2307130

Variant names:

• chr1-99851033-A-G
• rs2307130
• NM_000642.3:c.-10A>G

Your query was ambiguous. Multiple possible variants found:

• chr1-99851033-A-G
• chr1-99851033-A-T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.-10A>G variant causes a 5 prime UTR premature start codon gain 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. 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 NM_000642.3 5_prime_UTR_premature_start_codon_gain
• Scores: Splicing: ADA: 0.0001780
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: 0.357
• Publications: 34 publications found

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 Gene-Disease associations (from GenCC):

• glycogen storage disease III

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Ambry Genetics, Laboratory for Molecular Medicine, Myriad Women’s Health, Orphanet, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 1-99851033-A-G is Benign according to our data. Variant chr1-99851033-A-G is described in ClinVar as Benign. ClinVar VariationId is 195096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.-10A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 34	ENST00000361915.8	NP_000633.2
AGL	NM_000642.3	c.-10A>G		5_prime_UTR_variant	Exon 2 of 34	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.-10A>G		5_prime_UTR_premature_start_codon_gain_variant	Exon 2 of 34	1	NM_000642.3	ENSP00000355106.3
AGL	ENST00000361915.8	c.-10A>G		5_prime_UTR_variant	Exon 2 of 34	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.419 AC: 63647 AN: 151976 Hom.: 14073 Cov.: 33

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

GnomAD2 exomes AF: 0.469 AC: 117972 AN: 251340 AF XY: 0.479

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 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.: 31 AF XY: 0.493 AC XY: 357476 AN XY: 725786

African (AFR) AF: 0.258 AC: 8622 AN: 33382

American (AMR) AF: 0.435 AC: 19460 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.398 AC: 10404 AN: 26114

East Asian (EAS) AF: 0.545 AC: 21611 AN: 39632

South Asian (SAS) AF: 0.538 AC: 46346 AN: 86202

European-Finnish (FIN) AF: 0.443 AC: 23680 AN: 53400

Middle Eastern (MID) AF: 0.371 AC: 2130 AN: 5740

European-Non Finnish (NFE) AF: 0.500 AC: 554774 AN: 1109108

Other (OTH) AF: 0.472 AC: 28448 AN: 60244

GnomAD4 genome AF: 0.419 AC: 63701 AN: 152094 Hom.: 14097 Cov.: 33 AF XY: 0.420 AC XY: 31205 AN XY: 74338

African (AFR) AF: 0.263 AC: 10915 AN: 41496

American (AMR) AF: 0.435 AC: 6646 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.395 AC: 1370 AN: 3472

East Asian (EAS) AF: 0.545 AC: 2814 AN: 5166

South Asian (SAS) AF: 0.545 AC: 2628 AN: 4824

European-Finnish (FIN) AF: 0.434 AC: 4579 AN: 10558

Middle Eastern (MID) AF: 0.350 AC: 103 AN: 294

European-Non Finnish (NFE) AF: 0.490 AC: 33328 AN: 67974

Other (OTH) AF: 0.431 AC: 910 AN: 2110

Alfa AF: 0.459 Hom.: 50876

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

Submissions by phenotype

Glycogen storage disease type III Benign:4

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Aug 01, 2017

Phosphorus, Inc.

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 24, 2014

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Dec 02, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

not provided Benign:2

Oct 22, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
CADD	Benign	13
DANN	Benign	0.82
PhyloP100		0.36
Mutation Taster		=46/54	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2307130; hg19: chr1-100316589; COSMIC: COSV54056176; COSMIC: COSV54056176;