rs146101365

chr3-148994232-G-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_004130.4(GYG1):c.98G>A(p.Arg33Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00191 in 1,613,892 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (5 hom.)
• Consequence: GYG1 NM_004130.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 3.09

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 Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.013021946).
• BP6: Variant 3-148994232-G-A is Benign according to our data. Variant chr3-148994232-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542121.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYG1	NM_004130.4	c.98G>A	p.Arg33Lys	missense_variant	2/8	ENST00000345003.9
GYG1	NM_001184720.2	c.98G>A	p.Arg33Lys	missense_variant	2/7
GYG1	NM_001184721.2	c.98G>A	p.Arg33Lys	missense_variant	2/6
GYG1	XM_017006275.2	c.-34-2070G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYG1	ENST00000345003.9	c.98G>A	p.Arg33Lys	missense_variant	2/8	1	NM_004130.4

Frequencies

GnomAD3 genomes AF: 0.00128 AC: 194 AN: 152068 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000217

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.000756

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00250

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00153 AC: 385 AN: 251448 Hom.: 1 AF XY: 0.00166 AC XY: 226 AN XY: 135912

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.000405

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000621

Gnomad FIN exome AF: 0.00134

Gnomad NFE exome AF: 0.00269

Gnomad OTH exome AF: 0.00179

GnomAD4 exome AF: 0.00198 AC: 2887 AN: 1461706 Hom.: 5 Cov.: 32 AF XY: 0.00199 AC XY: 1449 AN XY: 727160

Gnomad4 AFR exome AF: 0.000448

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000742

Gnomad4 FIN exome AF: 0.00131

Gnomad4 NFE exome AF: 0.00236

Gnomad4 OTH exome AF: 0.00137

GnomAD4 genome AF: 0.00127 AC: 194 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.000968 AC XY: 72 AN XY: 74402

Gnomad4 AFR AF: 0.000217

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000756

Gnomad4 NFE AF: 0.00250

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00200 Hom.: 0

Bravo AF: 0.00104

TwinsUK AF: 0.00189 AC: 7

ALSPAC AF: 0.00156 AC: 6

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00198 AC: 17

ExAC AF: 0.00175 AC: 212

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 30, 2019	- -
Uncertain significance, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -

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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.29	T;.;.;.;.;T
Eigen	Benign	-0.085
Eigen_PC	Benign	0.10
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.69	T;T;T;.;T;T
M_CAP	Benign	0.0072	T
MetaRNN	Benign	0.013	T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.88	L;.;L;.;L;.
MutationTaster	Benign	0.98	D;D;D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-2.1	N;.;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.21	T;.;T;T;T;T
Sift4G	Benign	0.21	T;T;T;T;T;T
Polyphen		0.10	B;B;B;B;.;.
Vest4		0.33
MVP		0.78
MPC		0.10
ClinPred		0.019	T
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.45
gMVP		0.55

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: rs146101365; hg19: chr3-148712019;