19-48970958-C-T

Position:

chr19-48970958-C-T

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_002103.5(GYS1):c.1615G>A(p.Glu539Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000449 in 1,613,958 control chromosomes in the GnomAD database, including 7 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 0.00028 ( 1 hom., cov: 31)

Exomes 𝑓: 0.00047 ( 6 hom. )

Consequence

GYS1
NM_002103.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: 2.68

Variant links:

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 links:

GYS1 (HGNC:):

GYS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0136882365).

BP6

Variant 19-48970958-C-T is Benign according to our data. Variant chr19-48970958-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 329810.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1, Benign=2}.

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000276 (42/152268) while in subpopulation SAS AF= 0.00478 (23/4814). AF 95% confidence interval is 0.00327. There are 1 homozygotes in gnomad4. There are 29 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GYS1	NM_002103.5 linkuse as main transcript	c.1615G>A	p.Glu539Lys	missense_variant	13/16	ENST00000323798.8	NP_002094.2	P13807-1
GYS1	NM_001161587.2 linkuse as main transcript	c.1423G>A	p.Glu475Lys	missense_variant	12/15		NP_001155059.1	P13807-2
GYS1	NR_027763.2 linkuse as main transcript	n.1630G>A		non_coding_transcript_exon_variant	12/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
GYS1	ENST00000323798.8 linkuse as main transcript	c.1615G>A	p.Glu539Lys	missense_variant	13/16	1	NM_002103.5	ENSP00000317904.3	P13807-1
GYS1	ENST00000263276.6 linkuse as main transcript	c.1423G>A	p.Glu475Lys	missense_variant	12/15	1		ENSP00000263276.6	P13807-2
GYS1	ENST00000472004.5 linkuse as main transcript	n.370G>A		non_coding_transcript_exon_variant	4/4	3
GYS1	ENST00000496048.1 linkuse as main transcript	n.522G>A		non_coding_transcript_exon_variant	5/5	3

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152150

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00477

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000191

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000895

AC:

225

AN:

251492

Hom.:

AF XY:

0.00119

AC XY:

162

AN XY:

135922

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00617

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000467

AC:

682

AN:

1461690

Hom.:

Cov.:

AF XY:

0.000660

AC XY:

480

AN XY:

727162

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.000201

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00639

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000657

Gnomad4 OTH exome

AF:

0.000547

GnomAD4 genome

AF:

0.000276

AC:

AN:

152268

Hom.:

Cov.:

AF XY:

0.000389

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00478

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000191

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.000175

Hom.:

Bravo

AF:

0.000155

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000997

AC:

121

Asia WGS

AF:

0.00260

AC:

AN:

3478

EpiCase

AF:

0.000273

EpiControl

AF:

0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Glycogen storage disease due to muscle and heart glycogen synthase deficiency

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 28, 2023	- -
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

- -

GYS1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 27, 2019

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

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 07, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Benign

-0.028

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.43

T;.

Eigen

Uncertain

0.32

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.82

LIST_S2

Uncertain

0.97

D;D

M_CAP

Benign

0.024

MetaRNN

Benign

0.014

T;T

MetaSVM

Benign

-0.70

MutationAssessor

Uncertain

2.1

M;.

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-1.6

N;N

REVEL

Uncertain

0.38

Sift

Benign

0.060

T;D

Sift4G

Benign

0.32

T;T

Polyphen

0.79

P;.

Vest4

0.64

MutPred

0.64

Gain of ubiquitination at E539 (P = 0.0192);.;

MVP

0.71

MPC

1.5

ClinPred

0.064

GERP RS

5.3

Varity_R

0.37

gMVP

0.82

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over