chr3-148996875-A-T

Variant names:

• chr3-148996875-A-T
• rs35054019
• NM_004130.4:c.452A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004130.4(GYG1):​c.452A>T​(p.His151Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00171 in 1,613,862 control chromosomes in the GnomAD database, including 54 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H151R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0091 (27 hom., cov: 32)
  • Exomes 𝑓: 0.00094 (27 hom.)
• Consequence: GYG1 NM_004130.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.25
• Publications: 2 publications found

Genes affected

GYG1 (HGNC:4699): (glycogenin 1) This gene encodes a member of the glycogenin family. Glycogenin is a glycosyltransferase that catalyzes the formation of a short glucose polymer from uridine diphosphate glucose in an autoglucosylation reaction. This reaction is followed by elongation and branching of the polymer, catalyzed by glycogen synthase and branching enzyme, to form glycogen. This gene is expressed in muscle and other tissues. Mutations in this gene result in glycogen storage disease XV. This gene has pseudogenes on chromosomes 1, 8 and 13 respectively. Alternatively spliced transcript variants encoding different isoforms have been identified.[provided by RefSeq, Sep 2010]

GYG1 Gene-Disease associations (from GenCC):

• polyglucosan body myopathy type 2

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet, Ambry Genetics
• glycogen storage disease XV

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0030701458).
• BP6: Variant 3-148996875-A-T is Benign according to our data. Variant chr3-148996875-A-T is described in ClinVar as Benign. ClinVar VariationId is 516905.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.0091 (1386/152284) while in subpopulation AFR AF = 0.0309 (1283/41536). AF 95% confidence interval is 0.0295. There are 27 homozygotes in GnomAd4. There are 672 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004130.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYG1	NM_004130.4	MANE Select	c.452A>T	p.His151Leu	missense	Exon 4 of 8	NP_004121.2
	GYG1	NM_001184720.2		c.452A>T	p.His151Leu	missense	Exon 4 of 7	NP_001171649.1	P46976-2
	GYG1	NM_001184721.2		c.452A>T	p.His151Leu	missense	Exon 4 of 6	NP_001171650.1	P46976-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GYG1	ENST00000345003.9	TSL:1 MANE Select	c.452A>T	p.His151Leu	missense	Exon 4 of 8	ENSP00000340736.4	P46976-1
	GYG1	ENST00000296048.10	TSL:1	c.452A>T	p.His151Leu	missense	Exon 4 of 7	ENSP00000296048.6	P46976-2
	GYG1	ENST00000484197.5	TSL:1	c.452A>T	p.His151Leu	missense	Exon 4 of 6	ENSP00000420683.1	P46976-3

Frequencies

GnomAD3 genomes AF: 0.00905 AC: 1377 AN: 152166 Hom.: 27 Cov.: 32

Gnomad AFR AF: 0.0307

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00511

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00958

GnomAD2 exomes AF: 0.00235 AC: 592 AN: 251448 AF XY: 0.00167

Gnomad AFR exome AF: 0.0314

Gnomad AMR exome AF: 0.00185

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000615

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000942 AC: 1377 AN: 1461578 Hom.: 27 Cov.: 31 AF XY: 0.000776 AC XY: 564 AN XY: 727118

African (AFR) AF: 0.0314 AC: 1050 AN: 33462

American (AMR) AF: 0.00219 AC: 98 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000115 AC: 3 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.000128 AC: 11 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00364 AC: 21 AN: 5766

European-Non Finnish (NFE) AF: 0.0000369 AC: 41 AN: 1111734

Other (OTH) AF: 0.00253 AC: 153 AN: 60392

GnomAD4 genome AF: 0.00910 AC: 1386 AN: 152284 Hom.: 27 Cov.: 32 AF XY: 0.00902 AC XY: 672 AN XY: 74490

African (AFR) AF: 0.0309 AC: 1283 AN: 41536

American (AMR) AF: 0.00510 AC: 78 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68026

Other (OTH) AF: 0.00948 AC: 20 AN: 2110

Alfa AF: 0.000561 Hom.: 0

Bravo AF: 0.0106

ESP6500AA AF: 0.0311 AC: 137

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00293 AC: 356

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Glycogen storage disease XV;C4015452:Polyglucosan body myopathy type 2 (2)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	10
DANN	Benign	0.86
DEOGEN2	Uncertain	0.51	D
Eigen	Benign	-0.81
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.32	N
LIST_S2	Uncertain	0.88	D
MetaRNN	Benign	0.0031	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.1	L
PhyloP100		1.2
PrimateAI	Benign	0.27	T
PROVEAN	Uncertain	-2.9	D
REVEL	Benign	0.20
Sift	Benign	0.031	D
Sift4G	Benign	0.090	T
Polyphen		0.0	B
Vest4		0.43
MVP		0.68
MPC		0.13
ClinPred		0.014	T
GERP RS		1.1
Varity_R		0.30
gMVP		0.61
Mutation Taster		=100/0	polymorphism

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: rs35054019; hg19: chr3-148714662;