1-99851045-G-C

Position:

• chr1-99851045-G-C

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000642.3(AGL):​c.3G>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: AGL NM_000642.3 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.96

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 Pathogenic. Variant got 12 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-99851045-G-C is Pathogenic according to our data. Variant chr1-99851045-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 551795.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
AGL	NM_000642.3	c.3G>C	p.Met1?	start_lost	2/34	ENST00000361915.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
AGL	ENST00000361915.8	c.3G>C	p.Met1?	start_lost	2/34	1	NM_000642.3	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease type III Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Counsyl

May 08, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.28
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.081	T;T;T;T
Eigen	Pathogenic	0.69
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	D;.;.;.
M_CAP	Pathogenic	0.42	D
MetaRNN	Pathogenic	0.99	D;D;D;D
MetaSVM	Uncertain	0.084	D
MutationTaster	Benign	1.0	D;D;D;D;D
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.61
Sift	Pathogenic	0.0	D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		0.99	D;D;D;D
Vest4		0.89
MutPred		0.98		Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);Gain of catalytic residue at M1 (P = 0.0065);
MVP		0.89
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.86
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1553181400; hg19: chr1-100316601;