rs886039873

Positions:

• chr1-99870507-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000642.3(AGL):​c.772T>C​(p.Ser258Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: AGL NM_000642.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.52

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.772T>C	p.Ser258Pro	missense_variant	6/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.772T>C	p.Ser258Pro	missense_variant	6/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease type III Pathogenic:1 Uncertain:1

Uncertain significance, criteria provided, single submitter	curation	Department Of Genetics, Sultan Qaboos University Hospital, Sultan Qaboos University	Dec 30, 2017	- -
Likely pathogenic, no assertion criteria provided	clinical testing	Bioscientia Institut fuer Medizinische Diagnostik GmbH, Sonic Healthcare	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.43	T;T;T;T;.
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.84	T;.;.;.;T
M_CAP	Benign	0.064	D
MetaRNN	Uncertain	0.71	D;D;D;D;D
MetaSVM	Uncertain	0.071	D
MutationAssessor	Uncertain	2.5	M;M;M;M;.
MutationTaster	Benign	0.98	D;D;D;D;D;D;D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.8	D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Benign	0.082	T;T;T;T;T
Sift4G	Benign	0.069	T;T;T;T;T
Polyphen		0.77	P;P;P;P;P
Vest4		0.57
MutPred		0.57		Gain of catalytic residue at S258 (P = 0.0035);Gain of catalytic residue at S258 (P = 0.0035);Gain of catalytic residue at S258 (P = 0.0035);Gain of catalytic residue at S258 (P = 0.0035);.;
MVP		0.92
MPC		0.18
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.61
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs886039873; hg19: chr1-100336063;