rs143137713

Variant names:

• chr3-148996462-G-C
• rs143137713
• NM_004130.4:c.304G>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 8P and 5B. PP5_Very_Strong BS1_Supporting BS2

The NM_004130.4(GYG1):​c.304G>C​(p.Asp102His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,613,688 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (2 hom.)
• Consequence: GYG1 NM_004130.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:16 U:3
• Conservation: PhyloP100: 9.57
• Publications: 17 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, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics
• glycogen storage disease XV

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PP5: Variant 3-148996462-G-C is Pathogenic according to our data. Variant chr3-148996462-G-C is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 162663.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00106 (161/152300) while in subpopulation AMR AF = 0.00203 (31/15296). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 74 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High Homozygotes in GnomAdExome4 at 2 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004130.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYG1	NM_004130.4	MANE Select	c.304G>C	p.Asp102His	missense	Exon 3 of 8	NP_004121.2
	GYG1	NM_001184720.2		c.304G>C	p.Asp102His	missense	Exon 3 of 7	NP_001171649.1	P46976-2
	GYG1	NM_001184721.2		c.304G>C	p.Asp102His	missense	Exon 3 of 6	NP_001171650.1	P46976-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYG1	ENST00000345003.9	TSL:1 MANE Select	c.304G>C	p.Asp102His	missense	Exon 3 of 8	ENSP00000340736.4	P46976-1
	GYG1	ENST00000296048.10	TSL:1	c.304G>C	p.Asp102His	missense	Exon 3 of 7	ENSP00000296048.6	P46976-2
	GYG1	ENST00000484197.5	TSL:1	c.304G>C	p.Asp102His	missense	Exon 3 of 6	ENSP00000420683.1	P46976-3

Frequencies

GnomAD3 genomes AF: 0.00106 AC: 161 AN: 152182 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00171

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.00102 AC: 257 AN: 251340 AF XY: 0.00101

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.000651

GnomAD4 exome AF: 0.00191 AC: 2787 AN: 1461388 Hom.: 2 Cov.: 31 AF XY: 0.00188 AC XY: 1368 AN XY: 727058

African (AFR) AF: 0.000329 AC: 11 AN: 33468

American (AMR) AF: 0.00130 AC: 58 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86250

European-Finnish (FIN) AF: 0.0000938 AC: 5 AN: 53278

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00237 AC: 2634 AN: 1111704

Other (OTH) AF: 0.00131 AC: 79 AN: 60378

GnomAD4 genome AF: 0.00106 AC: 161 AN: 152300 Hom.: 0 Cov.: 32 AF XY: 0.000994 AC XY: 74 AN XY: 74478

African (AFR) AF: 0.000265 AC: 11 AN: 41554

American (AMR) AF: 0.00203 AC: 31 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00171 AC: 116 AN: 68026

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.00154 Hom.: 0

Bravo AF: 0.00118

TwinsUK AF: 0.00270 AC: 10

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00186 AC: 16

ExAC AF: 0.000914 AC: 111

EpiCase AF: 0.00207

EpiControl AF: 0.00202

ClinVar

ClinVar submissions

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
4	2	-	not provided (6)
5	-	-	Polyglucosan body myopathy type 2 (5)
2	-	-	Glycogen storage disease XV (2)
2	-	-	Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 (2)
1	-	-	Acute rhabdomyolysis (1)
1	-	-	Glycogen storage disease (1)
1	-	-	GYG1-related disorder (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.21	D
BayesDel_noAF	Pathogenic	0.53
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	1.2
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.58	D
MetaRNN	Uncertain	0.61	D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.3	H
PhyloP100		9.6
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-6.8	D
REVEL	Pathogenic	0.94
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.99
MVP		1.0
MPC		0.56
ClinPred		0.89	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.98
gMVP		0.88
Mutation Taster		=0/100	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.14		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: rs143137713; hg19: chr3-148714249; COSMIC: COSV56049205; COSMIC: COSV56049205;