3-149026489-G-T

Variant names:

• chr3-149026489-G-T
• rs1553733613
• NM_004130.4:c.866G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_004130.4(GYG1):​c.866G>T​(p.Gly289Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G289S) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GYG1 NM_004130.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 8.07
• Publications: 0 publications found

Genes affected

GYG1 (HGNC:4699): (glycogenin 1) This gene encodes a member of the glycogenin family. Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction. This reaction is followed by elongation and branching of the polymer, catalyzed by glycogen synthase and branching enzyme, to form glycogen. This gene is expressed in muscle and other tissues. Mutations in this gene result in glycogen storage disease XV. This gene has pseudogenes on chromosomes 1, 8 and 13 respectively. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

GYG1 Gene-Disease associations (from GenCC):

• polyglucosan body myopathy type 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, PanelApp Australia, ClinGen
• glycogen storage disease XV

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae), Genomics England PanelApp

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYG1	NM_004130.4	c.866G>T	p.Gly289Val	missense_variant	Exon 7 of 8	ENST00000345003.9	NP_004121.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYG1	ENST00000345003.9	c.866G>T	p.Gly289Val	missense_variant	Exon 7 of 8	1	NM_004130.4	ENSP00000340736.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease XV Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Polyglucosan body myopathy type 2 Uncertain:1

Mar 05, 2018

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Uncertain	0.68
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.81	T
M_CAP	Benign	0.027	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.59	T
MutationAssessor	Benign	1.6	L
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.41
Sift	Benign	0.15	T
Sift4G	Uncertain	0.015	D
Polyphen		1.0	D
Vest4		0.62
MutPred		0.53		Gain of sheet (P = 0.0125);
MVP		0.89
MPC		0.24
ClinPred		0.63	D
GERP RS		5.6
Varity_R		0.29
gMVP		0.33
Mutation Taster		=45/55	disease causing

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

Other links and lift over

dbSNP: rs1553733613; hg19: chr3-148744276;