rs834575

Variant names:

• chr1-99902826-T-C
• rs834575
• NM_000642.3:c.3700+32T>C

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.3700+32T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0455 in 1,507,456 control chromosomes in the GnomAD database, including 1,769 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.052 (257 hom., cov: 32)
  • Exomes 𝑓: 0.045 (1512 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.243
• Publications: 2 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=-0.83).
• BP6: Variant 1-99902826-T-C is Benign according to our data. Variant chr1-99902826-T-C is described in ClinVar as Benign. ClinVar VariationId is 256742.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0774 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.3700+32T>C		intron_variant	Intron 27 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.3700+32T>C		intron_variant	Intron 27 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7943 AN: 152152 Hom.: 257 Cov.: 32

Gnomad AFR AF: 0.0797

Gnomad AMI AF: 0.0482

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.00923

Gnomad EAS AF: 0.0158

Gnomad SAS AF: 0.0457

Gnomad FIN AF: 0.0560

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0457

Gnomad OTH AF: 0.0445

GnomAD2 exomes AF: 0.0388 AC: 9382 AN: 241516 AF XY: 0.0389

Gnomad AFR exome AF: 0.0823

Gnomad AMR exome AF: 0.0155

Gnomad ASJ exome AF: 0.0103

Gnomad EAS exome AF: 0.00496

Gnomad FIN exome AF: 0.0536

Gnomad NFE exome AF: 0.0436

Gnomad OTH exome AF: 0.0365

GnomAD4 exome AF: 0.0448 AC: 60647 AN: 1355186 Hom.: 1512 Cov.: 19 AF XY: 0.0445 AC XY: 30205 AN XY: 679508

African (AFR) AF: 0.0840 AC: 2625 AN: 31232

American (AMR) AF: 0.0168 AC: 734 AN: 43712

Ashkenazi Jewish (ASJ) AF: 0.0117 AC: 296 AN: 25338

East Asian (EAS) AF: 0.0313 AC: 1222 AN: 39010

South Asian (SAS) AF: 0.0441 AC: 3687 AN: 83618

European-Finnish (FIN) AF: 0.0535 AC: 2822 AN: 52718

Middle Eastern (MID) AF: 0.0236 AC: 130 AN: 5516

European-Non Finnish (NFE) AF: 0.0460 AC: 46821 AN: 1017340

Other (OTH) AF: 0.0407 AC: 2310 AN: 56702

GnomAD4 genome AF: 0.0522 AC: 7941 AN: 152270 Hom.: 257 Cov.: 32 AF XY: 0.0514 AC XY: 3828 AN XY: 74448

African (AFR) AF: 0.0796 AC: 3307 AN: 41530

American (AMR) AF: 0.0300 AC: 458 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00923 AC: 32 AN: 3468

East Asian (EAS) AF: 0.0158 AC: 82 AN: 5188

South Asian (SAS) AF: 0.0452 AC: 218 AN: 4828

European-Finnish (FIN) AF: 0.0560 AC: 595 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0457 AC: 3111 AN: 68030

Other (OTH) AF: 0.0430 AC: 91 AN: 2114

Alfa AF: 0.0465 Hom.: 42

Bravo AF: 0.0486

Asia WGS AF: 0.0280 AC: 97 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease type III Benign:1

Jul 15, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	2.2
DANN	Benign	0.22
PhyloP100		0.24
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs834575; hg19: chr1-100368382;