rs147977213

Variant names:

• chr1-99891337-G-A
• rs147977213
• NM_000642.3:c.2930G>A
• AGL p.Arg977Gln

Your query was ambiguous. Multiple possible variants found:

• chr1-99891337-G-A
• chr1-99891337-G-T
• chr1-99891337-G-C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS1

The NM_000642.3(AGL):​c.2930G>A​(p.Arg977Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000973 in 1,613,558 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R977L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000095 (0 hom.)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 3.14
• Publications: 3 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: Laboratory for Molecular Medicine, Myriad Women's Health, Genomics England PanelApp, G2P, ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.039919227).
• BP6: Variant 1-99891337-G-A is Benign according to our data. Variant chr1-99891337-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 456478.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000118 (18/152122) while in subpopulation EAS AF = 0.00212 (11/5184). AF 95% confidence interval is 0.00119. There are 0 homozygotes in GnomAd4. There are 10 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

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.2930G>A	p.Arg977Gln	missense	Exon 22 of 34	NP_000633.2	P35573-1
	AGL	NM_000028.3		c.2930G>A	p.Arg977Gln	missense	Exon 22 of 34	NP_000019.2	P35573-1
	AGL	NM_000643.3		c.2930G>A	p.Arg977Gln	missense	Exon 22 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.2930G>A	p.Arg977Gln	missense	Exon 22 of 34	ENSP00000355106.3	P35573-1
	AGL	ENST00000294724.8	TSL:1	c.2930G>A	p.Arg977Gln	missense	Exon 22 of 34	ENSP00000294724.4	P35573-1
	AGL	ENST00000370163.7	TSL:1	c.2930G>A	p.Arg977Gln	missense	Exon 22 of 34	ENSP00000359182.3	P35573-1

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152004 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00212

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000883

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000956 AC: 24 AN: 251052 AF XY: 0.0000958

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000924

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000529

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000951 AC: 139 AN: 1461436 Hom.: 0 Cov.: 32 AF XY: 0.0000922 AC XY: 67 AN XY: 726994

African (AFR) AF: 0.00 AC: 0 AN: 33460

American (AMR) AF: 0.00 AC: 0 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26120

East Asian (EAS) AF: 0.00280 AC: 111 AN: 39676

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53364

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1111726

Other (OTH) AF: 0.0000166 AC: 1 AN: 60384

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10 AN XY: 74368

African (AFR) AF: 0.00 AC: 0 AN: 41494

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00212 AC: 11 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10600

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

European-Non Finnish (NFE) AF: 0.0000883 AC: 6 AN: 67954

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000756

Asia WGS AF: 0.000289 AC: 1 AN: 3476

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Glycogen storage disease type III (3)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Uncertain	-0.050
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.036	T
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.040	T
MetaSVM	Benign	-0.78	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		3.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.040	N
REVEL	Benign	0.23
Sift	Benign	0.28	T
Sift4G	Benign	0.31	T
Varity_R		0.34
gMVP		0.62
Mutation Taster		=74/26	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs147977213;

hg19: chr1-100356893;

COSMIC: COSV54051490;