chr19-48968563-G-A

Variant names:

• chr19-48968563-G-A
• rs1042265
• NM_002103.5:c.*725C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002103.5(GYS1):​c.*725C>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.095 in 454,382 control chromosomes in the GnomAD database, including 2,262 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.097 (763 hom., cov: 32)
  • Exomes 𝑓: 0.094 (1499 hom.)
• Consequence: GYS1 NM_002103.5 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.153
• Publications: 19 publications found

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]

GYS1 Gene-Disease associations (from GenCC):

• glycogen storage disease due to muscle and heart glycogen synthase deficiency

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

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.68).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.132 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GYS1	NM_002103.5	c.*725C>T		3_prime_UTR_variant	Exon 16 of 16	ENST00000323798.8	NP_002094.2
GYS1	NR_027763.2	n.2954C>T		non_coding_transcript_exon_variant	Exon 15 of 15
GYS1	NM_001161587.2	c.*725C>T		3_prime_UTR_variant	Exon 15 of 15		NP_001155059.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798.8	c.*725C>T		3_prime_UTR_variant	Exon 16 of 16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000263276.6	c.*725C>T		3_prime_UTR_variant	Exon 15 of 15	1		ENSP00000263276.6

Frequencies

GnomAD3 genomes AF: 0.0970 AC: 14754 AN: 152066 Hom.: 763 Cov.: 32

Gnomad AFR AF: 0.0936

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.137

Gnomad ASJ AF: 0.0839

Gnomad EAS AF: 0.0507

Gnomad SAS AF: 0.0573

Gnomad FIN AF: 0.0610

Gnomad MID AF: 0.0949

Gnomad NFE AF: 0.102

Gnomad OTH AF: 0.109

GnomAD2 exomes AF: 0.0989 AC: 13477 AN: 136236 AF XY: 0.0933

Gnomad AFR exome AF: 0.0955

Gnomad AMR exome AF: 0.162

Gnomad ASJ exome AF: 0.0805

Gnomad EAS exome AF: 0.0541

Gnomad FIN exome AF: 0.0647

Gnomad NFE exome AF: 0.103

Gnomad OTH exome AF: 0.0886

GnomAD4 exome AF: 0.0940 AC: 28417 AN: 302198 Hom.: 1499 Cov.: 0 AF XY: 0.0893 AC XY: 15384 AN XY: 172246

African (AFR) AF: 0.0984 AC: 842 AN: 8554

American (AMR) AF: 0.162 AC: 4419 AN: 27274

Ashkenazi Jewish (ASJ) AF: 0.0810 AC: 874 AN: 10786

East Asian (EAS) AF: 0.0514 AC: 473 AN: 9210

South Asian (SAS) AF: 0.0578 AC: 3447 AN: 59650

European-Finnish (FIN) AF: 0.0622 AC: 794 AN: 12756

Middle Eastern (MID) AF: 0.107 AC: 123 AN: 1150

European-Non Finnish (NFE) AF: 0.102 AC: 16184 AN: 158768

Other (OTH) AF: 0.0898 AC: 1261 AN: 14050

GnomAD4 genome AF: 0.0970 AC: 14765 AN: 152184 Hom.: 763 Cov.: 32 AF XY: 0.0947 AC XY: 7044 AN XY: 74392

African (AFR) AF: 0.0938 AC: 3896 AN: 41532

American (AMR) AF: 0.136 AC: 2085 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.0839 AC: 291 AN: 3470

East Asian (EAS) AF: 0.0504 AC: 261 AN: 5178

South Asian (SAS) AF: 0.0577 AC: 278 AN: 4814

European-Finnish (FIN) AF: 0.0610 AC: 647 AN: 10606

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.102 AC: 6922 AN: 67994

Other (OTH) AF: 0.109 AC: 229 AN: 2110

Alfa AF: 0.0940 Hom.: 660

Bravo AF: 0.104

Asia WGS AF: 0.0780 AC: 269 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

May 12, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hereditary hyperferritinemia with congenital cataracts Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neuroferritinopathy Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Glycogen storage disease due to muscle and heart glycogen synthase deficiency Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.9
DANN	Benign	0.79
PhyloP100		-0.15
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1042265; hg19: chr19-49471820;