3-148991643-G-C

Position:

• chr3-148991643-G-C

Variant summary

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

The NM_004130.4(GYG1):​c.3G>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000717 in 1,394,474 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: GYG1 NM_004130.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.0100

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 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 3-148991643-G-C is Pathogenic according to our data. Variant chr3-148991643-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1477393.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYG1	NM_004130.4	c.3G>C	p.Met1?	start_lost	1/8	ENST00000345003.9	NP_004121.2
GYG1	NM_001184720.2	c.3G>C	p.Met1?	start_lost	1/7		NP_001171649.1
GYG1	NM_001184721.2	c.3G>C	p.Met1?	start_lost	1/6		NP_001171650.1
GYG1	XM_017006275.2	c.-39G>C		5_prime_UTR_variant	1/6		XP_016861764.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYG1	ENST00000345003.9	c.3G>C	p.Met1?	start_lost	1/8	1	NM_004130.4	ENSP00000340736

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 7.17e-7 AC: 1 AN: 1394474 Hom.: 0 Cov.: 30 AF XY: 0.00000145 AC XY: 1 AN XY: 689852

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.20e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jun 30, 2021

In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Disruption of the initiator codon has been observed in individual(s) with polyglucosan body myopathy (PMID: 27544502). This sequence change affects the initiator methionine of the GYG1 mRNA. The next in-frame methionine is located at codon 47. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the ExAC database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.010
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.22	T;.;.;.;.;T
Eigen	Benign	0.0041
Eigen_PC	Benign	0.036
FATHMM_MKL	Benign	0.76	D
LIST_S2	Uncertain	0.90	D;D;D;.;D;D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.98	D;D;D;D;D;D
MetaSVM	Uncertain	-0.26	T
MutationTaster	Benign	1.0	D;D;D;D
PROVEAN	Benign	-0.020	N;.;N;N;N;N
REVEL	Uncertain	0.53
Sift	Uncertain	0.021	D;.;D;D;D;D
Sift4G	Benign	0.074	T;T;T;T;T;T
Polyphen		0.25	B;P;P;P;.;.
Vest4		0.27
MutPred		0.99		Gain of catalytic residue at M1 (P = 0.0401);Gain of catalytic residue at M1 (P = 0.0401);Gain of catalytic residue at M1 (P = 0.0401);Gain of catalytic residue at M1 (P = 0.0401);Gain of catalytic residue at M1 (P = 0.0401);Gain of catalytic residue at M1 (P = 0.0401);
MVP		0.89
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.72
gMVP		0.41

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: rs1365446658; hg19: chr3-148709430;