1-99892547-C-T

Variant names:

• chr1-99892547-C-T
• rs3753494
• NM_000642.3:c.3199C>T

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.3199C>T​(p.Pro1067Ser) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.14 in 1,612,830 control chromosomes in the GnomAD database, including 16,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1067L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1508 hom., cov: 32)
  • Exomes 𝑓: 0.14 (15018 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 7.28
• Publications: 30 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034675002).
• BP6: Variant 1-99892547-C-T is Benign according to our data. Variant chr1-99892547-C-T is described in ClinVar as Benign. ClinVar VariationId is 256734.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.144 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.3199C>T	p.Pro1067Ser	missense	Exon 24 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.3199C>T	p.Pro1067Ser	missense	Exon 24 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.3199C>T	p.Pro1067Ser	missense	Exon 24 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.3199C>T	p.Pro1067Ser	missense	Exon 24 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.3199C>T	p.Pro1067Ser	missense	Exon 24 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.3199C>T	p.Pro1067Ser	missense	Exon 24 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.136 AC: 20704 AN: 151914 Hom.: 1507 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.221

Gnomad AMR AF: 0.127

Gnomad ASJ AF: 0.182

Gnomad EAS AF: 0.0262

Gnomad SAS AF: 0.149

Gnomad FIN AF: 0.169

Gnomad MID AF: 0.193

Gnomad NFE AF: 0.146

Gnomad OTH AF: 0.148

GnomAD2 exomes AF: 0.134 AC: 33763 AN: 251154 AF XY: 0.138

Gnomad AFR exome AF: 0.117

Gnomad AMR exome AF: 0.0998

Gnomad ASJ exome AF: 0.191

Gnomad EAS exome AF: 0.0294

Gnomad FIN exome AF: 0.167

Gnomad NFE exome AF: 0.150

Gnomad OTH exome AF: 0.148

GnomAD4 exome AF: 0.141 AC: 205269 AN: 1460798 Hom.: 15018 Cov.: 33 AF XY: 0.141 AC XY: 102608 AN XY: 726728

African (AFR) AF: 0.119 AC: 3984 AN: 33442

American (AMR) AF: 0.105 AC: 4681 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.186 AC: 4844 AN: 26104

East Asian (EAS) AF: 0.0303 AC: 1201 AN: 39614

South Asian (SAS) AF: 0.144 AC: 12420 AN: 86230

European-Finnish (FIN) AF: 0.169 AC: 9024 AN: 53402

Middle Eastern (MID) AF: 0.233 AC: 1341 AN: 5762

European-Non Finnish (NFE) AF: 0.143 AC: 159327 AN: 1111210

Other (OTH) AF: 0.140 AC: 8447 AN: 60350

GnomAD4 genome AF: 0.136 AC: 20697 AN: 152032 Hom.: 1508 Cov.: 32 AF XY: 0.137 AC XY: 10206 AN XY: 74308

African (AFR) AF: 0.120 AC: 4983 AN: 41508

American (AMR) AF: 0.126 AC: 1930 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.182 AC: 632 AN: 3468

East Asian (EAS) AF: 0.0263 AC: 136 AN: 5174

South Asian (SAS) AF: 0.150 AC: 722 AN: 4820

European-Finnish (FIN) AF: 0.169 AC: 1789 AN: 10566

Middle Eastern (MID) AF: 0.180 AC: 53 AN: 294

European-Non Finnish (NFE) AF: 0.146 AC: 9945 AN: 67920

Other (OTH) AF: 0.145 AC: 306 AN: 2104

Alfa AF: 0.139 Hom.: 5273

Bravo AF: 0.129

TwinsUK AF: 0.137 AC: 508

ALSPAC AF: 0.142 AC: 548

ESP6500AA AF: 0.126 AC: 557

ESP6500EA AF: 0.146 AC: 1257

ExAC AF: 0.136 AC: 16506

Asia WGS AF: 0.0940 AC: 327 AN: 3476

EpiCase AF: 0.157

EpiControl AF: 0.157

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	Glycogen storage disease type III (4)
-	-	2	not provided (2)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	23
DANN	Benign	0.97
DEOGEN2	Benign	0.22	T
Eigen	Benign	-0.021
Eigen_PC	Benign	0.034
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0035	T
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L
PhyloP100		7.3
PrimateAI	Uncertain	0.55	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.29
Sift	Uncertain	0.027	D
Sift4G	Uncertain	0.048	D
Polyphen		0.15	B
Vest4		0.42
MPC		0.048
ClinPred		0.078	T
GERP RS		5.2
Varity_R		0.17
gMVP		0.67
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs3753494; hg19: chr1-100358103; COSMIC: COSV107319744;