1-99851081-C-T

Variant names:

• chr1-99851081-C-T
• rs138203039
• NM_000642.3:c.39C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_000646.3(AGL):​c.-153C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000825 in 1,614,036 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00067 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00084 (12 hom.)
• Consequence: AGL NM_000646.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 1.35
• Publications: 2 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: Orphanet, Myriad Women’s Health, Genomics England PanelApp, ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Laboratory for Molecular Medicine, G2P

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 1-99851081-C-T is Benign according to our data. Variant chr1-99851081-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 287104.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00067 (102/152286) while in subpopulation SAS AF = 0.00827 (40/4834). AF 95% confidence interval is 0.00625. There are 1 homozygotes in GnomAd4. There are 52 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000646.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	NM_000642.3	MANE Select	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 34	NP_000633.2	P35573-1
	AGL	NM_000646.3		c.-153C>T		5_prime_UTR_premature_start_codon_gain	Exon 2 of 35	NP_000637.2	P35573-3
	AGL	NM_000028.3		c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 34	NP_000019.2	P35573-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.39C>T	p.Asn13Asn	synonymous	Exon 2 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.000670 AC: 102 AN: 152168 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000916

Gnomad ASJ AF: 0.00317

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000470

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00140 AC: 351 AN: 251458 AF XY: 0.00171

Gnomad AFR exome AF: 0.0000615

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000277

Gnomad NFE exome AF: 0.000589

Gnomad OTH exome AF: 0.000815

GnomAD4 exome AF: 0.000841 AC: 1230 AN: 1461750 Hom.: 12 Cov.: 33 AF XY: 0.00103 AC XY: 751 AN XY: 727174

African (AFR) AF: 0.0000598 AC: 2 AN: 33472

American (AMR) AF: 0.000268 AC: 12 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00276 AC: 72 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39662

South Asian (SAS) AF: 0.00748 AC: 645 AN: 86254

European-Finnish (FIN) AF: 0.000318 AC: 17 AN: 53416

Middle Eastern (MID) AF: 0.00416 AC: 24 AN: 5764

European-Non Finnish (NFE) AF: 0.000360 AC: 400 AN: 1111944

Other (OTH) AF: 0.000960 AC: 58 AN: 60388

GnomAD4 genome AF: 0.000670 AC: 102 AN: 152286 Hom.: 1 Cov.: 33 AF XY: 0.000698 AC XY: 52 AN XY: 74474

African (AFR) AF: 0.0000241 AC: 1 AN: 41552

American (AMR) AF: 0.000915 AC: 14 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00317 AC: 11 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00827 AC: 40 AN: 4834

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10600

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000470 AC: 32 AN: 68022

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000416 Hom.: 0

Bravo AF: 0.000397

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease type III (4)
-	-	3	not provided (3)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	13
DANN	Benign	0.88
PhyloP100		1.4
Mutation Taster		=297/3	polymorphism

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: rs138203039; hg19: chr1-100316637; COSMIC: COSV99649097; COSMIC: COSV99649097;