rs1800305

Variant names:

• chr17-80109992-C-T
• rs1800305
• NM_000152.5:c.1374C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_000152.5(GAA):​c.1374C>T​(p.Tyr458Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0689 in 1,613,054 control chromosomes in the GnomAD database, including 4,799 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.097 (946 hom., cov: 34)
  • Exomes 𝑓: 0.066 (3853 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: -1.31
• Publications: 17 publications found

Genes affected

GAA (HGNC:4065): (alpha glucosidase) This gene encodes lysosomal alpha-glucosidase, which is essential for the degradation of glycogen to glucose in lysosomes. The encoded preproprotein is proteolytically processed to generate multiple intermediate forms and the mature form of the enzyme. Defects in this gene are the cause of glycogen storage disease II, also known as Pompe's disease, which is an autosomal recessive disorder with a broad clinical spectrum. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

GAA Gene-Disease associations (from GenCC):

• glycogen storage disease II

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, G2P
• glycogen storage disease due to acid maltase deficiency, infantile onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet
• glycogen storage disease due to acid maltase deficiency, late-onset

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 17-80109992-C-T is Benign according to our data. Variant chr17-80109992-C-T is described in ClinVar as Benign. ClinVar VariationId is 92463.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.31 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.187 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000152.5. 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
	GAA	NM_000152.5	MANE Select	c.1374C>T	p.Tyr458Tyr	synonymous	Exon 9 of 20	NP_000143.2
	GAA	NM_001079803.3		c.1374C>T	p.Tyr458Tyr	synonymous	Exon 10 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.1374C>T	p.Tyr458Tyr	synonymous	Exon 9 of 20	NP_001073272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.1374C>T	p.Tyr458Tyr	synonymous	Exon 9 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.1374C>T	p.Tyr458Tyr	synonymous	Exon 10 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.1374C>T	p.Tyr458Tyr	synonymous	Exon 9 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0974 AC: 14825 AN: 152154 Hom.: 945 Cov.: 34

Gnomad AFR AF: 0.191

Gnomad AMI AF: 0.0702

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0709

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0739

Gnomad FIN AF: 0.0632

Gnomad MID AF: 0.142

Gnomad NFE AF: 0.0661

Gnomad OTH AF: 0.0969

GnomAD2 exomes AF: 0.0693 AC: 17332 AN: 250176 AF XY: 0.0692

Gnomad AFR exome AF: 0.196

Gnomad AMR exome AF: 0.0456

Gnomad ASJ exome AF: 0.0719

Gnomad EAS exome AF: 0.000817

Gnomad FIN exome AF: 0.0603

Gnomad NFE exome AF: 0.0652

Gnomad OTH exome AF: 0.0800

GnomAD4 exome AF: 0.0659 AC: 96273 AN: 1460782 Hom.: 3853 Cov.: 32 AF XY: 0.0667 AC XY: 48438 AN XY: 726722

African (AFR) AF: 0.202 AC: 6762 AN: 33468

American (AMR) AF: 0.0489 AC: 2188 AN: 44706

Ashkenazi Jewish (ASJ) AF: 0.0713 AC: 1862 AN: 26130

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39694

South Asian (SAS) AF: 0.0863 AC: 7444 AN: 86236

European-Finnish (FIN) AF: 0.0622 AC: 3278 AN: 52662

Middle Eastern (MID) AF: 0.129 AC: 743 AN: 5764

European-Non Finnish (NFE) AF: 0.0626 AC: 69603 AN: 1111754

Other (OTH) AF: 0.0724 AC: 4373 AN: 60368

GnomAD4 genome AF: 0.0974 AC: 14830 AN: 152272 Hom.: 946 Cov.: 34 AF XY: 0.0962 AC XY: 7162 AN XY: 74460

African (AFR) AF: 0.190 AC: 7909 AN: 41530

American (AMR) AF: 0.0546 AC: 835 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.0709 AC: 246 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5182

South Asian (SAS) AF: 0.0740 AC: 357 AN: 4824

European-Finnish (FIN) AF: 0.0632 AC: 671 AN: 10616

Middle Eastern (MID) AF: 0.143 AC: 42 AN: 294

European-Non Finnish (NFE) AF: 0.0661 AC: 4498 AN: 68022

Other (OTH) AF: 0.0955 AC: 202 AN: 2116

Alfa AF: 0.0997 Hom.: 713

Bravo AF: 0.100

Asia WGS AF: 0.0420 AC: 148 AN: 3478

EpiCase AF: 0.0689

EpiControl AF: 0.0679

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	5	Glycogen storage disease, type II (5)
-	-	3	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	0.21
DANN	Benign	0.89
PhyloP100		-1.3
Mutation Taster		=98/2	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: rs1800305; hg19: chr17-78083791;