19-48968987-C-T

Position:

• chr19-48968987-C-T

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP6 BS1 BS2

The NM_002103.5(GYS1):​c.*301G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00281 in 611,936 control chromosomes in the GnomAD database, including 13 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 0.0019 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0031 (12 hom.)
• Consequence: GYS1 NM_002103.5 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:2
• Conservation: PhyloP100: 0.249

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -11 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.44).
• BP6: Variant 19-48968987-C-T is Benign according to our data. Variant chr19-48968987-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329801.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00185 (282/152346) while in subpopulation SAS AF= 0.00704 (34/4832). AF 95% confidence interval is 0.00518. There are 1 homozygotes in gnomad4. There are 146 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS1	NM_002103.5	c.*301G>A		3_prime_UTR_variant	16/16	ENST00000323798.8	NP_002094.2
GYS1	NM_001161587.2	c.*301G>A		3_prime_UTR_variant	15/15		NP_001155059.1
GYS1	NR_027763.2	n.2530G>A		non_coding_transcript_exon_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GYS1	ENST00000323798	c.*301G>A		3_prime_UTR_variant	16/16	1	NM_002103.5	ENSP00000317904.3
GYS1	ENST00000263276	c.*301G>A		3_prime_UTR_variant	15/15	1		ENSP00000263276.6

Frequencies

GnomAD3 genomes AF: 0.00185 AC: 282 AN: 152228 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000555

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00703

Gnomad FIN AF: 0.000941

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00198

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00331 AC: 450 AN: 136062 Hom.: 2 AF XY: 0.00384 AC XY: 284 AN XY: 73928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00222

Gnomad ASJ exome AF: 0.00641

Gnomad EAS exome AF: 0.0000959

Gnomad SAS exome AF: 0.00957

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00181

Gnomad OTH exome AF: 0.00654

GnomAD4 exome AF: 0.00313 AC: 1437 AN: 459590 Hom.: 12 Cov.: 0 AF XY: 0.00366 AC XY: 919 AN XY: 250752

Gnomad4 AFR exome AF: 0.000654

Gnomad4 AMR exome AF: 0.00190

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00963

Gnomad4 FIN exome AF: 0.000364

Gnomad4 NFE exome AF: 0.00202

Gnomad4 OTH exome AF: 0.00384

GnomAD4 genome AF: 0.00185 AC: 282 AN: 152346 Hom.: 1 Cov.: 32 AF XY: 0.00196 AC XY: 146 AN XY: 74498

Gnomad4 AFR AF: 0.000553

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.00662

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00704

Gnomad4 FIN AF: 0.000941

Gnomad4 NFE AF: 0.00198

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00240 Hom.: 0

Bravo AF: 0.00182

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:2

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

- -

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	-0.44
CADD	Benign	13
DANN	Benign	0.93

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: rs147489255; hg19: chr19-49472244;