1-99875226-G-T

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.1155G>T(p.Lys385Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0126 in 1,614,052 control chromosomes in the GnomAD database, including 180 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. K385K) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.013 (24 hom., cov: 33)
  • Exomes 𝑓: 0.013 (156 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: 0.784

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 (MetaRNN=0.0034376383).
• BP6: Variant 1-99875226-G-T is Benign according to our data. Variant chr1-99875226-G-T is described in ClinVar as [Likely_benign]. Clinvar id is 256719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-99875226-G-T is described in Lovd as [Benign]. Variant chr1-99875226-G-T is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0126 (1925/152328) while in subpopulation NFE AF= 0.0152 (1034/68022). AF 95% confidence interval is 0.0144. There are 24 homozygotes in gnomad4. There are 979 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 24 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.1155G>T	p.Lys385Asn	missense_variant	9/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.1155G>T	p.Lys385Asn	missense_variant	9/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes AF: 0.0127 AC: 1927 AN: 152210 Hom.: 24 Cov.: 33

Gnomad AFR AF: 0.00239

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0143

Gnomad ASJ AF: 0.0294

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.0359

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0211

GnomAD3 exomes AF: 0.0135 AC: 3375 AN: 250696 Hom.: 35 AF XY: 0.0135 AC XY: 1830 AN XY: 135732

Gnomad AFR exome AF: 0.00176

Gnomad AMR exome AF: 0.00645

Gnomad ASJ exome AF: 0.0286

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.00363

Gnomad FIN exome AF: 0.0340

Gnomad NFE exome AF: 0.0165

Gnomad OTH exome AF: 0.0192

GnomAD4 exome AF: 0.0126 AC: 18416 AN: 1461724 Hom.: 156 Cov.: 32 AF XY: 0.0127 AC XY: 9219 AN XY: 727156

Gnomad4 AFR exome AF: 0.00299

Gnomad4 AMR exome AF: 0.00736

Gnomad4 ASJ exome AF: 0.0290

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00422

Gnomad4 FIN exome AF: 0.0345

Gnomad4 NFE exome AF: 0.0125

Gnomad4 OTH exome AF: 0.0142

GnomAD4 genome AF: 0.0126 AC: 1925 AN: 152328 Hom.: 24 Cov.: 33 AF XY: 0.0131 AC XY: 979 AN XY: 74492

Gnomad4 AFR AF: 0.00238

Gnomad4 AMR AF: 0.0142

Gnomad4 ASJ AF: 0.0294

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.0359

Gnomad4 NFE AF: 0.0152

Gnomad4 OTH AF: 0.0208

Alfa AF: 0.0147 Hom.: 50

Bravo AF: 0.0102

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.0135 AC: 52

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.0155 AC: 133

ExAC AF: 0.0140 AC: 1698

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.0167

EpiControl AF: 0.0160

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease type III Benign:6

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, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jul 15, 2021	- -
Benign, no assertion criteria provided	clinical testing	Natera, Inc.	Sep 16, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	Oct 09, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 14, 2017	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Oct 31, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 10, 2016	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	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.40
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.45
Cadd	Benign	14
Dann	Benign	0.94
DEOGEN2	Benign	0.057	T;T;T;T;.
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	T;.;.;.;T
MetaRNN	Benign	0.0034	T;T;T;T;T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L;L;L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N;N;N;N;N
REVEL	Benign	0.25
Sift	Benign	0.084	T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T
Polyphen		0.18	B;B;B;B;B
Vest4		0.14
MutPred		0.30		Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);Loss of ubiquitination at K385 (P = 0.0098);.;
MPC		0.060
ClinPred		0.011	T
GERP RS		-0.33
Varity_R		0.11
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs28730701; hg19: chr1-100340782;