1-99875226-G-T

Variant names:

• chr1-99875226-G-T
• rs28730701
• NM_000642.3:c.1155G>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.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. 15/21 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:13
• Conservation: PhyloP100: 0.784
• Publications: 11 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=0.0034376383).
• BP6: Variant 1-99875226-G-T is Benign according to our data. Variant chr1-99875226-G-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 256719.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 24 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.1155G>T	p.Lys385Asn	missense	Exon 9 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.1155G>T	p.Lys385Asn	missense	Exon 9 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.1155G>T	p.Lys385Asn	missense	Exon 9 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.1155G>T	p.Lys385Asn	missense	Exon 9 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.1155G>T	p.Lys385Asn	missense	Exon 9 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.1155G>T	p.Lys385Asn	missense	Exon 9 of 34	ENSP00000359182.3	P35573-1

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

GnomAD2 exomes AF: 0.0135 AC: 3375 AN: 250696 AF XY: 0.0135

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 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

African (AFR) AF: 0.00299 AC: 100 AN: 33476

American (AMR) AF: 0.00736 AC: 329 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.0290 AC: 758 AN: 26130

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39678

South Asian (SAS) AF: 0.00422 AC: 364 AN: 86252

European-Finnish (FIN) AF: 0.0345 AC: 1842 AN: 53414

Middle Eastern (MID) AF: 0.0447 AC: 258 AN: 5768

European-Non Finnish (NFE) AF: 0.0125 AC: 13908 AN: 1111898

Other (OTH) AF: 0.0142 AC: 856 AN: 60394

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

African (AFR) AF: 0.00238 AC: 99 AN: 41588

American (AMR) AF: 0.0142 AC: 218 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.0294 AC: 102 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00435 AC: 21 AN: 4826

European-Finnish (FIN) AF: 0.0359 AC: 381 AN: 10604

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1034 AN: 68022

Other (OTH) AF: 0.0208 AC: 44 AN: 2112

Alfa AF: 0.0137 Hom.: 84

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease type III (6)
-	-	5	not provided (5)
-	-	2	not specified (2)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.76
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.83	T
MetaRNN	Benign	0.0034	T
MetaSVM	Benign	-0.66	T
MutationAssessor	Benign	1.7	L
PhyloP100		0.78
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.25
Sift	Benign	0.084	T
Sift4G	Benign	0.12	T
Polyphen		0.18	B
Vest4		0.14
MutPred		0.30		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
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs28730701; hg19: chr1-100340782;