19-48968420-T-C

Position:

• chr19-48968420-T-C

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM2 BP4_Moderate BP6 BS1

The NM_002103.5(GYS1):​c.*868A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000957 in 454,456 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00083 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (1 hom.)
• Consequence: GYS1 NM_002103.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 0.778

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 Likely_benign. Variant got -5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 19-48968420-T-C is Benign according to our data. Variant chr19-48968420-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329793.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000828 (126/152214) while in subpopulation NFE AF= 0.00151 (103/68002). AF 95% confidence interval is 0.00128. There are 0 homozygotes in gnomad4. There are 57 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GYS1	NM_002103.5	c.*868A>G		3_prime_UTR_variant	16/16	ENST00000323798.8
GYS1	NM_001161587.2	c.*868A>G		3_prime_UTR_variant	15/15
GYS1	NR_027763.2	n.3097A>G		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GYS1	ENST00000323798.8	c.*868A>G		3_prime_UTR_variant	16/16	1	NM_002103.5	P1
GYS1	ENST00000263276.6	c.*868A>G		3_prime_UTR_variant	15/15	1

Frequencies

GnomAD3 genomes AF: 0.000809 AC: 123 AN: 152096 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00151

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000930 AC: 127 AN: 136570 Hom.: 0 AF XY: 0.000930 AC XY: 69 AN XY: 74178

Gnomad AFR exome AF: 0.000310

Gnomad AMR exome AF: 0.000245

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000845

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00182

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00102 AC: 309 AN: 302242 Hom.: 1 Cov.: 0 AF XY: 0.000969 AC XY: 167 AN XY: 172262

Gnomad4 AFR exome AF: 0.000585

Gnomad4 AMR exome AF: 0.000220

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000821

Gnomad4 FIN exome AF: 0.000234

Gnomad4 NFE exome AF: 0.00152

Gnomad4 OTH exome AF: 0.000356

GnomAD4 genome AF: 0.000828 AC: 126 AN: 152214 Hom.: 0 Cov.: 32 AF XY: 0.000766 AC XY: 57 AN XY: 74442

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00124

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00151

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.000737

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Hereditary hyperferritinemia with congenital cataracts Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

FTL-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 17, 2021

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Neuroferritinopathy Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.31
CADD	Benign	13
DANN	Benign	0.81
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs571576339; hg19: chr19-49471677;