rs548255

chr1-99900897-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000642.3(AGL):c.3588+36T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0141 in 1,519,308 control chromosomes in the GnomAD database, including 276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.019 (44 hom., cov: 30)
  • Exomes 𝑓: 0.014 (232 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.305

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=-0.88).
• BP6: Variant 1-99900897-T-G is Benign according to our data. Variant chr1-99900897-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 256740.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0192 (2912/151966) while in subpopulation AFR AF= 0.0252 (1047/41476). AF 95% confidence interval is 0.024. There are 44 homozygotes in gnomad4. There are 1426 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 45 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.3588+36T>G		intron_variant		ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.3588+36T>G		intron_variant		1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2917 AN: 151848 Hom.: 45 Cov.: 30

Gnomad AFR AF: 0.0253

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0159

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00477

Gnomad FIN AF: 0.0364

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0153

Gnomad OTH AF: 0.0249

GnomAD3 exomes AF: 0.0160 AC: 3695 AN: 230674 Hom.: 95 AF XY: 0.0158 AC XY: 1969 AN XY: 124846

Gnomad AFR exome AF: 0.0258

Gnomad AMR exome AF: 0.00779

Gnomad ASJ exome AF: 0.0294

Gnomad EAS exome AF: 0.0000591

Gnomad SAS exome AF: 0.00478

Gnomad FIN exome AF: 0.0349

Gnomad NFE exome AF: 0.0171

Gnomad OTH exome AF: 0.0218

GnomAD4 exome AF: 0.0135 AC: 18495 AN: 1367342 Hom.: 232 Cov.: 24 AF XY: 0.0135 AC XY: 9240 AN XY: 683938

Gnomad4 AFR exome AF: 0.0266

Gnomad4 AMR exome AF: 0.00850

Gnomad4 ASJ exome AF: 0.0292

Gnomad4 EAS exome AF: 0.0000255

Gnomad4 SAS exome AF: 0.00484

Gnomad4 FIN exome AF: 0.0351

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.0161

GnomAD4 genome AF: 0.0192 AC: 2912 AN: 151966 Hom.: 44 Cov.: 30 AF XY: 0.0192 AC XY: 1426 AN XY: 74318

Gnomad4 AFR AF: 0.0252

Gnomad4 AMR AF: 0.0158

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00456

Gnomad4 FIN AF: 0.0364

Gnomad4 NFE AF: 0.0153

Gnomad4 OTH AF: 0.0246

Alfa AF: 0.0224 Hom.: 33

Bravo AF: 0.0175

Asia WGS AF: 0.00578 AC: 20 AN: 3474

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Nov 29, 2019

- -

Glycogen storage disease type III Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
Cadd	Benign	0.37
Dann	Benign	0.14

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

Publications

LitVar

Other links and lift over

dbSNP: rs548255; hg19: chr1-100366453;