1-99881185-T-C

Variant names:

• chr1-99881185-T-C
• rs3736296
• NM_000642.3:c.2001+8T>C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.2001+8T>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 1,612,570 control chromosomes in the GnomAD database, including 245,309 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 0.52 (20668 hom., cov: 31)
  • Exomes 𝑓: 0.55 (224641 hom.)
• Consequence: AGL NM_000642.3 splice_region, intron
• Scores: Splicing: ADA: 0.00003241
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.08

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-99881185-T-C is Benign according to our data. Variant chr1-99881185-T-C is described in ClinVar as [Benign]. Clinvar id is 256725.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99881185-T-C is described in Lovd as [Benign].
• 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.2001+8T>C		splice_region_variant, intron_variant	Intron 15 of 33	ENST00000361915.8	NP_000633.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8	c.2001+8T>C		splice_region_variant, intron_variant	Intron 15 of 33	1	NM_000642.3	ENSP00000355106.3

Frequencies

GnomAD3 genomes AF: 0.516 AC: 78283 AN: 151780 Hom.: 20631 Cov.: 31

Gnomad AFR AF: 0.425

Gnomad AMI AF: 0.464

Gnomad AMR AF: 0.565

Gnomad ASJ AF: 0.419

Gnomad EAS AF: 0.675

Gnomad SAS AF: 0.599

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.443

Gnomad NFE AF: 0.547

Gnomad OTH AF: 0.515

GnomAD3 exomes AF: 0.554 AC: 139035 AN: 250904 Hom.: 39215 AF XY: 0.553 AC XY: 75041 AN XY: 135590

Gnomad AFR exome AF: 0.431

Gnomad AMR exome AF: 0.622

Gnomad ASJ exome AF: 0.423

Gnomad EAS exome AF: 0.660

Gnomad SAS exome AF: 0.589

Gnomad FIN exome AF: 0.514

Gnomad NFE exome AF: 0.544

Gnomad OTH exome AF: 0.541

GnomAD4 exome AF: 0.552 AC: 806886 AN: 1460672 Hom.: 224641 Cov.: 37 AF XY: 0.553 AC XY: 401532 AN XY: 726678

Gnomad4 AFR exome AF: 0.425

Gnomad4 AMR exome AF: 0.612

Gnomad4 ASJ exome AF: 0.432

Gnomad4 EAS exome AF: 0.676

Gnomad4 SAS exome AF: 0.590

Gnomad4 FIN exome AF: 0.523

Gnomad4 NFE exome AF: 0.552

Gnomad4 OTH exome AF: 0.534

GnomAD4 genome AF: 0.516 AC: 78361 AN: 151898 Hom.: 20668 Cov.: 31 AF XY: 0.518 AC XY: 38423 AN XY: 74230

Gnomad4 AFR AF: 0.425

Gnomad4 AMR AF: 0.565

Gnomad4 ASJ AF: 0.419

Gnomad4 EAS AF: 0.675

Gnomad4 SAS AF: 0.600

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.547

Gnomad4 OTH AF: 0.522

Alfa AF: 0.533 Hom.: 16112

Bravo AF: 0.515

Asia WGS AF: 0.633 AC: 2202 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

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. -

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

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

- -

Jul 14, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:2

-

PreventionGenetics, part of Exact Sciences

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	-0.83
CADD	Benign	7.4
DANN	Benign	0.56

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000032
dbscSNV1_RF	Benign	0.0020
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

Other links and lift over

dbSNP: rs3736296; hg19: chr1-100346741; COSMIC: COSV54049713; COSMIC: COSV54049713;