3-148991642-T-A

Position:

chr3-148991642-T-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1PS1_ModeratePM2

The NM_004130.4(GYG1):c.2T>A(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 0.00000323 in 1,547,736 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 Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000029 ( 0 hom. )

Consequence

GYG1
NM_004130.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.884

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 12 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_004130.4 (GYG1) was described as [Likely_pathogenic] in ClinVar as 1477393

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
GYG1	NM_004130.4 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/8	ENST00000345003.9
GYG1	NM_001184720.2 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/7
GYG1	NM_001184721.2 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/6
GYG1	XM_017006275.2 linkuse as main transcript	c.-40T>A		5_prime_UTR_variant	1/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYG1	ENST00000345003.9 linkuse as main transcript	c.2T>A	p.Met1?	start_lost	1/8	1	NM_004130.4		P46976-1

Frequencies

GnomAD3 genomes

AF:

0.00000661

AC:

AN:

151308

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000669

AC:

AN:

149492

Hom.:

AF XY:

0.0000121

AC XY:

AN XY:

82668

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000163

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000286

AC:

AN:

1396428

Hom.:

Cov.:

AF XY:

0.00000434

AC XY:

AN XY:

690992

show subpopulations

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:

0.00000368

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000661

AC:

AN:

151308

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

73932

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2022

Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. 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. ClinVar contains an entry for this variant (Variation ID: 1508529). Disruption of the initiator codon has been observed in individual(s) with GYG1-related conditions (PMID: 27544502). This variant is present in population databases (no rsID available, gnomAD 0.002%). This sequence change affects the initiator methionine of the GYG1 mRNA. The next in-frame methionine is located at codon 47. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.62

BayesDel_noAF

Uncertain

0.080

CADD

Uncertain

DANN

Uncertain

0.98

DEOGEN2

Benign

0.39

T;.;.;.;.;T

Eigen

Benign

0.18

Eigen_PC

Benign

0.12

FATHMM_MKL

Benign

0.71

LIST_S2

Uncertain

0.90

D;D;D;.;D;D

M_CAP

Pathogenic

0.99

MetaRNN

Pathogenic

0.98

D;D;D;D;D;D

MetaSVM

Uncertain

0.032

MutationTaster

Benign

1.0

D;D;D;D

PROVEAN

Uncertain

-2.8

D;.;D;D;D;D

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0010

D;.;D;D;D;D

Sift4G

Uncertain

0.0020

D;D;D;D;D;D

Polyphen

0.76

P;D;D;D;.;.

Vest4

0.40

MutPred

0.98

Gain of ubiquitination at M1 (P = 0.0267);Gain of ubiquitination at M1 (P = 0.0267);Gain of ubiquitination at M1 (P = 0.0267);Gain of ubiquitination at M1 (P = 0.0267);Gain of ubiquitination at M1 (P = 0.0267);Gain of ubiquitination at M1 (P = 0.0267);

MVP

0.94

ClinPred

0.99

GERP RS

2.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.96

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over