1-99876493-C-T

Variant names:

• chr1-99876493-C-T
• rs149771710
• NM_000642.3:c.1319C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000642.3(AGL):​c.1319C>T​(p.Ser440Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00057 in 1,609,728 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S440Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0031 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00031 (4 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.06
• Publications: 1 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 (MetaRNN=0.005627334).
• BP6: Variant 1-99876493-C-T is Benign according to our data. Variant chr1-99876493-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256721.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 = 0.00307 (467/152222) while in subpopulation AFR AF = 0.0106 (441/41518). AF 95% confidence interval is 0.0098. There are 1 homozygotes in GnomAd4. There are 222 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 4 AR gene

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.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	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.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.1319C>T	p.Ser440Phe	missense	Exon 11 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.00307 AC: 467 AN: 152104 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0107

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000813 AC: 204 AN: 250896 AF XY: 0.000619

Gnomad AFR exome AF: 0.0112

Gnomad AMR exome AF: 0.000521

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000491

GnomAD4 exome AF: 0.000309 AC: 451 AN: 1457506 Hom.: 4 Cov.: 29 AF XY: 0.000270 AC XY: 196 AN XY: 725424

African (AFR) AF: 0.0105 AC: 349 AN: 33368

American (AMR) AF: 0.000761 AC: 34 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26094

East Asian (EAS) AF: 0.00 AC: 0 AN: 39626

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86164

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5758

European-Non Finnish (NFE) AF: 0.0000162 AC: 18 AN: 1108118

Other (OTH) AF: 0.000763 AC: 46 AN: 60276

GnomAD4 genome AF: 0.00307 AC: 467 AN: 152222 Hom.: 1 Cov.: 32 AF XY: 0.00298 AC XY: 222 AN XY: 74428

African (AFR) AF: 0.0106 AC: 441 AN: 41518

American (AMR) AF: 0.00144 AC: 22 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4810

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68018

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000931 Hom.: 1

Bravo AF: 0.00363

ESP6500AA AF: 0.00931 AC: 41

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000964 AC: 117

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glycogen storage disease type III (2)
-	-	2	not provided (2)
-	-	1	Inborn genetic diseases (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.37
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.097	T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.65	T
MetaRNN	Benign	0.0056	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.1
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Benign	0.032	D
Sift4G	Uncertain	0.038	D
Polyphen		0.20	B
Vest4		0.44
MVP		0.78
MPC		0.055
ClinPred		0.020	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.059
gMVP		0.45
Mutation Taster		=100/0	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: rs149771710; hg19: chr1-100342049;