rs5458

Positions:

• chr19-48987266-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_002103.5(GYS1):​c.420A>G​(p.Gly140=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00322 in 1,613,178 control chromosomes in the GnomAD database, including 89 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (30 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (59 hom.)
• Consequence: GYS1 NM_002103.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.201

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 19-48987266-T-C is Benign according to our data. Variant chr19-48987266-T-C is described in ClinVar as [Benign]. Clinvar id is 329824.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.201 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0121 (1838/152208) while in subpopulation AFR AF= 0.0367 (1524/41518). AF 95% confidence interval is 0.0352. There are 30 homozygotes in gnomad4. There are 835 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 30 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS1	NM_002103.5	c.420A>G	p.Gly140=	synonymous_variant	3/16	ENST00000323798.8
GYS1	NM_001161587.2	c.301-1231A>G		intron_variant
GYS1	NR_027763.2	n.435A>G		non_coding_transcript_exon_variant	2/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS1	ENST00000323798.8	c.420A>G	p.Gly140=	synonymous_variant	3/16	1	NM_002103.5	P1
GYS1	ENST00000263276.6	c.301-1231A>G		intron_variant		1
GYS1	ENST00000457974.1	n.646A>G		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes AF: 0.0120 AC: 1832 AN: 152090 Hom.: 30 Cov.: 32

Gnomad AFR AF: 0.0367

Gnomad AMI AF: 0.00329

Gnomad AMR AF: 0.00629

Gnomad ASJ AF: 0.0378

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000823

Gnomad OTH AF: 0.0119

GnomAD3 exomes AF: 0.00487 AC: 1211 AN: 248812 Hom.: 22 AF XY: 0.00395 AC XY: 531 AN XY: 134508

Gnomad AFR exome AF: 0.0398

Gnomad AMR exome AF: 0.00337

Gnomad ASJ exome AF: 0.0338

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000331

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000826

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00230 AC: 3359 AN: 1460970 Hom.: 59 Cov.: 31 AF XY: 0.00215 AC XY: 1565 AN XY: 726654

Gnomad4 AFR exome AF: 0.0403

Gnomad4 AMR exome AF: 0.00332

Gnomad4 ASJ exome AF: 0.0333

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000931

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000535

Gnomad4 OTH exome AF: 0.00610

GnomAD4 genome AF: 0.0121 AC: 1838 AN: 152208 Hom.: 30 Cov.: 32 AF XY: 0.0112 AC XY: 835 AN XY: 74428

Gnomad4 AFR AF: 0.0367

Gnomad4 AMR AF: 0.00628

Gnomad4 ASJ AF: 0.0378

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000823

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00777 Hom.: 15

Bravo AF: 0.0143

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.00120

EpiControl AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Dec 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 18, 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.52

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: rs5458; hg19: chr19-49490523;