rs5447

Positions:

• chr19-48977986-T-C

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002103.5(GYS1):​c.1246A>G​(p.Met416Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00969 in 1,613,926 control chromosomes in the GnomAD database, including 426 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.015 (67 hom., cov: 31)
  • Exomes 𝑓: 0.0092 (359 hom.)
• Consequence: GYS1 NM_002103.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.35

Genes affected

GYS1 (HGNC:4706): (glycogen synthase 1) The protein encoded by this gene catalyzes the addition of glucose monomers to the growing glycogen molecule through the formation of alpha-1,4-glycoside linkages. Mutations in this gene are associated with muscle glycogen storage disease. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2009]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027920902).
• BP6: Variant 19-48977986-T-C is Benign according to our data. Variant chr19-48977986-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 329814.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr19-48977986-T-C is described in Lovd as [Benign]. Variant chr19-48977986-T-C is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0925 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS1	NM_002103.5	c.1246A>G	p.Met416Val	missense_variant	10/16	ENST00000323798.8
GYS1	NM_001161587.2	c.1054A>G	p.Met352Val	missense_variant	9/15
GYS1	NR_027763.2	n.1261A>G		non_coding_transcript_exon_variant	9/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS1	ENST00000323798.8	c.1246A>G	p.Met416Val	missense_variant	10/16	1	NM_002103.5	P1
GYS1	ENST00000263276.6	c.1054A>G	p.Met352Val	missense_variant	9/15	1
GYS1	ENST00000472004.5	n.1A>G		non_coding_transcript_exon_variant	1/4	3
GYS1	ENST00000496048.1	n.153A>G		non_coding_transcript_exon_variant	2/5	3

Frequencies

GnomAD3 genomes AF: 0.0148 AC: 2253 AN: 152040 Hom.: 66 Cov.: 31

Gnomad AFR AF: 0.0143

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00295

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.0994

Gnomad SAS AF: 0.0211

Gnomad FIN AF: 0.0616

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.0105

GnomAD3 exomes AF: 0.0190 AC: 4768 AN: 251470 Hom.: 167 AF XY: 0.0185 AC XY: 2511 AN XY: 135906

Gnomad AFR exome AF: 0.0138

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00456

Gnomad EAS exome AF: 0.106

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.0593

Gnomad NFE exome AF: 0.00468

Gnomad OTH exome AF: 0.0160

GnomAD4 exome AF: 0.00915 AC: 13378 AN: 1461768 Hom.: 359 Cov.: 31 AF XY: 0.00948 AC XY: 6891 AN XY: 727190

Gnomad4 AFR exome AF: 0.0134

Gnomad4 AMR exome AF: 0.00228

Gnomad4 ASJ exome AF: 0.00406

Gnomad4 EAS exome AF: 0.103

Gnomad4 SAS exome AF: 0.0192

Gnomad4 FIN exome AF: 0.0563

Gnomad4 NFE exome AF: 0.00293

Gnomad4 OTH exome AF: 0.0111

GnomAD4 genome AF: 0.0149 AC: 2265 AN: 152158 Hom.: 67 Cov.: 31 AF XY: 0.0180 AC XY: 1339 AN XY: 74376

Gnomad4 AFR AF: 0.0143

Gnomad4 AMR AF: 0.00295

Gnomad4 ASJ AF: 0.00433

Gnomad4 EAS AF: 0.0997

Gnomad4 SAS AF: 0.0214

Gnomad4 FIN AF: 0.0616

Gnomad4 NFE AF: 0.00451

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00808 Hom.: 62

Bravo AF: 0.0107

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00519 AC: 20

ESP6500AA AF: 0.0145 AC: 64

ESP6500EA AF: 0.00360 AC: 31

ExAC AF: 0.0187 AC: 2274

Asia WGS AF: 0.0530 AC: 183 AN: 3478

EpiCase AF: 0.00245

EpiControl AF: 0.00261

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 06, 2016	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Aug 17, 2017	- -

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.065
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	20
DANN	Benign	0.96
DEOGEN2	Benign	0.34	T;.
Eigen	Benign	-0.17
Eigen_PC	Benign	0.0093
FATHMM_MKL	Uncertain	0.78	D
LIST_S2	Uncertain	0.88	D;D
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.46	N;.
MutationTaster	Benign	0.0013	P;P;P;P;P
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-0.89	N;N
REVEL	Benign	0.13
Sift	Benign	0.27	T;T
Sift4G	Benign	0.29	T;T
Polyphen		0.0040	B;.
Vest4		0.055
MPC		0.49
ClinPred		0.0079	T
GERP RS		5.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.19
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: rs5447; hg19: chr19-49481243;