3-148991645-C-G

Position:

• chr3-148991645-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_004130.4(GYG1):​c.5C>G​(p.Thr2Arg) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/23 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: GYG1 NM_004130.4 missense, splice_region
• Scores: Splicing: ADA: 0.009127
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a modified_residue N-acetylthreonine (size 0) in uniprot entity GLYG_HUMAN
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36108708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYG1	NM_004130.4	c.5C>G	p.Thr2Arg	missense_variant, splice_region_variant	1/8	ENST00000345003.9
GYG1	NM_001184720.2	c.5C>G	p.Thr2Arg	missense_variant, splice_region_variant	1/7
GYG1	NM_001184721.2	c.5C>G	p.Thr2Arg	missense_variant, splice_region_variant	1/6
GYG1	XM_017006275.2	c.-37C>G		splice_region_variant, 5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYG1	ENST00000345003.9	c.5C>G	p.Thr2Arg	missense_variant, splice_region_variant	1/8	1	NM_004130.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Mar 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. This variant has not been reported in the literature in individuals affected with GYG1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces threonine, which is neutral and polar, with arginine, which is basic and polar, at codon 2 of the GYG1 protein (p.Thr2Arg). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.062	T
BayesDel_noAF	Benign	-0.33
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.32	T;.;.;.;.;T
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.76	D
LIST_S2	Benign	0.84	T;T;T;.;T;T
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.36	T;T;T;T;T;T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.4	L;.;L;.;L;.
MutationTaster	Benign	0.54	N;N;N;N
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-2.7	D;.;D;D;D;D
REVEL	Benign	0.081
Sift	Uncertain	0.0050	D;.;D;D;D;D
Sift4G	Uncertain	0.033	D;T;T;T;D;T
Polyphen		0.20	B;P;B;P;.;.
Vest4		0.14
MutPred		0.37		Loss of catalytic residue at T2 (P = 0.0778);Loss of catalytic residue at T2 (P = 0.0778);Loss of catalytic residue at T2 (P = 0.0778);Loss of catalytic residue at T2 (P = 0.0778);Loss of catalytic residue at T2 (P = 0.0778);Loss of catalytic residue at T2 (P = 0.0778);
MVP		0.71
MPC		0.11
ClinPred		0.83	D
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.46
gMVP		0.34

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0091
dbscSNV1_RF	Benign	0.19
SpliceAI score (max)		0.11		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-148709432;