1-99881185-T-C

Position:

chr1-99881185-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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

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:

AGL (HGNC:):

AGL links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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/exons	MANE	Protein	UniProt
AGL	NM_000642.3 linkuse as main transcript	c.2001+8T>C		splice_region_variant, intron_variant		ENST00000361915.8	NP_000633.2	P35573-1A0A0S2A4E4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
AGL	ENST00000361915.8 linkuse as main transcript	c.2001+8T>C		splice_region_variant, intron_variant		1	NM_000642.3	ENSP00000355106.3		P35573-1

Frequencies

GnomAD3 genomes

AF:

0.516

AC:

78283

AN:

151780

Hom.:

20631

Cov.:

show subpopulations

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

show subpopulations

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.:

AF XY:

0.553

AC XY:

401532

AN XY:

726678

show subpopulations

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.:

AF XY:

0.518

AC XY:

38423

AN XY:

74230

show subpopulations

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

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	Genome-Nilou Lab	Jul 14, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -

not specified

Benign:2

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	PreventionGenetics, part of Exact Sciences	-	- -

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

-0.83

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

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