rs2035961

Variant names:

• chr1-99891585-T-A
• rs2035961
• NM_000642.3:c.2950-21T>A

Your query was ambiguous. Multiple possible variants found:

• chr1-99891585-T-A
• chr1-99891585-T-C
• chr1-99891585-T-G

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.2950-21T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.534 in 1,611,376 control chromosomes in the GnomAD database, including 232,599 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.49 (18798 hom., cov: 31)
  • Exomes 𝑓: 0.54 (213801 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.0910
• Publications: 9 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=-0.8).
• BP6: Variant 1-99891585-T-A is Benign according to our data. Variant chr1-99891585-T-A is described in ClinVar as Benign. ClinVar VariationId is 256733.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
AGL	NM_000642.3	c.2950-21T>A		intron_variant	Intron 22 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.2950-21T>A		intron_variant	Intron 22 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.489 AC: 74232 AN: 151708 Hom.: 18763 Cov.: 31

Gnomad AFR AF: 0.376

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.545

Gnomad ASJ AF: 0.388

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.593

Gnomad FIN AF: 0.485

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.531

Gnomad OTH AF: 0.487

GnomAD2 exomes AF: 0.537 AC: 134648 AN: 250876 AF XY: 0.537

Gnomad AFR exome AF: 0.380

Gnomad AMR exome AF: 0.613

Gnomad ASJ exome AF: 0.395

Gnomad EAS exome AF: 0.659

Gnomad FIN exome AF: 0.479

Gnomad NFE exome AF: 0.527

Gnomad OTH exome AF: 0.519

GnomAD4 exome AF: 0.538 AC: 785552 AN: 1459550 Hom.: 213801 Cov.: 40 AF XY: 0.538 AC XY: 391027 AN XY: 726170

African (AFR) AF: 0.370 AC: 12342 AN: 33398

American (AMR) AF: 0.602 AC: 26894 AN: 44642

Ashkenazi Jewish (ASJ) AF: 0.403 AC: 10522 AN: 26104

East Asian (EAS) AF: 0.676 AC: 26769 AN: 39628

South Asian (SAS) AF: 0.585 AC: 50468 AN: 86202

European-Finnish (FIN) AF: 0.488 AC: 26022 AN: 53362

Middle Eastern (MID) AF: 0.385 AC: 2213 AN: 5752

European-Non Finnish (NFE) AF: 0.540 AC: 599129 AN: 1110172

Other (OTH) AF: 0.517 AC: 31193 AN: 60290

GnomAD4 genome AF: 0.489 AC: 74307 AN: 151826 Hom.: 18798 Cov.: 31 AF XY: 0.491 AC XY: 36454 AN XY: 74212

African (AFR) AF: 0.376 AC: 15559 AN: 41430

American (AMR) AF: 0.546 AC: 8319 AN: 15240

Ashkenazi Jewish (ASJ) AF: 0.388 AC: 1347 AN: 3468

East Asian (EAS) AF: 0.674 AC: 3485 AN: 5168

South Asian (SAS) AF: 0.594 AC: 2864 AN: 4820

European-Finnish (FIN) AF: 0.485 AC: 5104 AN: 10530

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.532 AC: 36067 AN: 67858

Other (OTH) AF: 0.494 AC: 1040 AN: 2106

Alfa AF: 0.499 Hom.: 3540

Bravo AF: 0.490

Asia WGS AF: 0.626 AC: 2176 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

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 14, 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	-0.80
CADD	Benign	5.5
DANN	Benign	0.51
PhyloP100		0.091
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs2035961; hg19: chr1-100357141; COSMIC: COSV54051217;