chr1-99875271-T-C

Variant names:

• chr1-99875271-T-C
• rs17121466
• NM_000642.3:c.1185+15T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000642.3(AGL):​c.1185+15T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0255 in 1,612,916 control chromosomes in the GnomAD database, including 700 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (52 hom., cov: 33)
  • Exomes 𝑓: 0.026 (648 hom.)
• Consequence: AGL NM_000642.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 3.10
• Publications: 5 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: Ambry Genetics, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Laboratory for Molecular Medicine, Myriad Women’s Health

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 1-99875271-T-C is Benign according to our data. Variant chr1-99875271-T-C is described in ClinVar as Benign. ClinVar VariationId is 256720.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0633 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000642.3. 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.1185+15T>C		intron	N/A	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.1185+15T>C		intron	N/A	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.1185+15T>C		intron	N/A	NP_000634.2	A0A0S2A4E4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	AGL	ENST00000361915.8	TSL:1 MANE Select	c.1185+15T>C		intron	N/A	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.1185+15T>C		intron	N/A	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.1185+15T>C		intron	N/A	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.0209 AC: 3177 AN: 152216 Hom.: 52 Cov.: 33

Gnomad AFR AF: 0.00454

Gnomad AMI AF: 0.0373

Gnomad AMR AF: 0.0415

Gnomad ASJ AF: 0.0211

Gnomad EAS AF: 0.0327

Gnomad SAS AF: 0.0697

Gnomad FIN AF: 0.00979

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0220

GnomAD2 exomes AF: 0.0308 AC: 7718 AN: 250610 AF XY: 0.0330

Gnomad AFR exome AF: 0.00495

Gnomad AMR exome AF: 0.0405

Gnomad ASJ exome AF: 0.0243

Gnomad EAS exome AF: 0.0366

Gnomad FIN exome AF: 0.00993

Gnomad NFE exome AF: 0.0237

Gnomad OTH exome AF: 0.0337

GnomAD4 exome AF: 0.0260 AC: 38009 AN: 1460582 Hom.: 648 Cov.: 31 AF XY: 0.0276 AC XY: 20071 AN XY: 726666

African (AFR) AF: 0.00416 AC: 139 AN: 33446

American (AMR) AF: 0.0389 AC: 1740 AN: 44696

Ashkenazi Jewish (ASJ) AF: 0.0233 AC: 608 AN: 26120

East Asian (EAS) AF: 0.0198 AC: 785 AN: 39668

South Asian (SAS) AF: 0.0719 AC: 6197 AN: 86232

European-Finnish (FIN) AF: 0.0115 AC: 615 AN: 53416

Middle Eastern (MID) AF: 0.0269 AC: 155 AN: 5768

European-Non Finnish (NFE) AF: 0.0236 AC: 26236 AN: 1110906

Other (OTH) AF: 0.0254 AC: 1534 AN: 60330

GnomAD4 genome AF: 0.0209 AC: 3184 AN: 152334 Hom.: 52 Cov.: 33 AF XY: 0.0224 AC XY: 1667 AN XY: 74496

African (AFR) AF: 0.00455 AC: 189 AN: 41576

American (AMR) AF: 0.0419 AC: 641 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0211 AC: 73 AN: 3466

East Asian (EAS) AF: 0.0326 AC: 169 AN: 5188

South Asian (SAS) AF: 0.0694 AC: 335 AN: 4828

European-Finnish (FIN) AF: 0.00979 AC: 104 AN: 10622

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0233 AC: 1583 AN: 68030

Other (OTH) AF: 0.0232 AC: 49 AN: 2114

Alfa AF: 0.0232 Hom.: 25

Bravo AF: 0.0210

Asia WGS AF: 0.0440 AC: 152 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	Glycogen storage disease type III (3)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	13
DANN	Benign	0.60
PhyloP100		3.1
Mutation Taster		=100/0	polymorphism (auto)

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: rs17121466; hg19: chr1-100340827;