NM_000152.5:c.2109C>T

Variant names:

• chr17-80113286-C-T
• rs150728610
• NM_000152.5:c.2109C>T

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Moderate BP6 BP7

The NM_000152.5(GAA):​c.2109C>T​(p.Tyr703Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000681 in 1,599,862 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00035 (0 hom., cov: 34)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:6
• Conservation: PhyloP100: 2.45
• Publications: 1 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, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.3).
• BP6: Variant 17-80113286-C-T is Benign according to our data. Variant chr17-80113286-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 291223.
• BP7: Synonymous conserved (PhyloP=2.45 with no splicing effect.

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.2109C>T	p.Tyr703Tyr	synonymous	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2109C>T	p.Tyr703Tyr	synonymous	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2109C>T	p.Tyr703Tyr	synonymous	Exon 15 of 20	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2109C>T	p.Tyr703Tyr	synonymous	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2109C>T	p.Tyr703Tyr	synonymous	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2124C>T	p.Tyr708Tyr	synonymous	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000348 AC: 53 AN: 152198 Hom.: 0 Cov.: 34

Gnomad AFR AF: 0.00121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000725 AC: 16 AN: 220610 AF XY: 0.0000504

Gnomad AFR exome AF: 0.000886

Gnomad AMR exome AF: 0.0000939

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000102

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000387 AC: 56 AN: 1447546 Hom.: 0 Cov.: 35 AF XY: 0.0000292 AC XY: 21 AN XY: 718728

African (AFR) AF: 0.00132 AC: 44 AN: 33212

American (AMR) AF: 0.0000931 AC: 4 AN: 42968

Ashkenazi Jewish (ASJ) AF: 0.0000778 AC: 2 AN: 25708

East Asian (EAS) AF: 0.00 AC: 0 AN: 38962

South Asian (SAS) AF: 0.0000120 AC: 1 AN: 83520

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51950

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00000271 AC: 3 AN: 1105650

Other (OTH) AF: 0.0000334 AC: 2 AN: 59828

GnomAD4 genome AF: 0.000348 AC: 53 AN: 152316 Hom.: 0 Cov.: 34 AF XY: 0.000282 AC XY: 21 AN XY: 74474

African (AFR) AF: 0.00120 AC: 50 AN: 41568

American (AMR) AF: 0.0000653 AC: 1 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000473 AC: 1 AN: 2112

Alfa AF: 0.000383 Hom.: 0

Bravo AF: 0.000446

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	3	Glycogen storage disease, type II (4)
-	1	1	not provided (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	GAA-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.30
CADD	Benign	5.7
DANN	Benign	0.94
PhyloP100		2.5
Mutation Taster		=84/16	polymorphism

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

Other links and lift over

dbSNP: rs150728610; hg19: chr17-78087085;