chr17-80112907-T-G

Variant names:

• chr17-80112907-T-G
• rs144090460
• NM_000152.5:c.1920T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP7 BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.1920T>G variant in GAA is a synonymous (silent) variant that does not change the encoded amino acid (p.Pro640=) and is not predicted to impact splicing. This variant has not been reported as disease-causing in an individual with Pompe disease. It has been described as a polymorphism in a cohort of patients with infantile or juvenile-onset Pompe disease from Taiwan (PMID:18458862). It was also reported in two patients in a European cohort with limb-girdle muscle weakness without a second variant (PMID:29149851). Thus, there is insufficient data to apply PP4. The highest population minor allele frequency in gnomAD v3.1.2 is [0.001534] (8/5184 alleles) in East Asian population. This is higher than the ClinGen Lysosomal Diseases VCEP’s threshold for PM2_Supporting (<0.001), and lower than the threshold for BS1 (>0.005). Therefore none of the population data codes are met. This variant is a synonymous (silent) variant that is not predicted by SpliceAI to impact splicing. In addition, it occurs at a nucleotide that is not conserved as shown by PhyloP100 (-2.182) and PhastCons (0.000) (BP4, BP7). There is a ClinVar entry for this variant (Variation ID: 255358; 1-star review status) with 10 submitters classifying the variant as uncertain significance (4) or likely benign (6). In summary, this variant meets the criteria to be classified as likely benign for Pompe disease based on the ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases Variant Curation Expert panel (Specifications Version 2.0): BP4, BP7.(Classification approved by the ClinGen Lysosomal Diseases Variant Curation Expert Panel on May 7, 2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815546/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00014 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00010 (0 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:9
• Conservation: PhyloP100: -2.18
• Publications: 2 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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BP7: For more information check the summary or visit ClinGen Evidence Repository.

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.1920T>G	p.Pro640Pro	synonymous	Exon 14 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1920T>G	p.Pro640Pro	synonymous	Exon 15 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1920T>G	p.Pro640Pro	synonymous	Exon 14 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.1920T>G	p.Pro640Pro	synonymous	Exon 14 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1920T>G	p.Pro640Pro	synonymous	Exon 15 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1935T>G	p.Pro645Pro	synonymous	Exon 14 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152164 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000181 AC: 44 AN: 242468 AF XY: 0.000152

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000994

Gnomad FIN exome AF: 0.000387

Gnomad NFE exome AF: 0.000146

Gnomad OTH exome AF: 0.000168

GnomAD4 exome AF: 0.000102 AC: 149 AN: 1458230 Hom.: 0 Cov.: 33 AF XY: 0.000120 AC XY: 87 AN XY: 725054

African (AFR) AF: 0.00 AC: 0 AN: 33456

American (AMR) AF: 0.00 AC: 0 AN: 44424

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.000555 AC: 22 AN: 39652

South Asian (SAS) AF: 0.0000585 AC: 5 AN: 85488

European-Finnish (FIN) AF: 0.000496 AC: 26 AN: 52392

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.0000810 AC: 90 AN: 1110802

Other (OTH) AF: 0.0000996 AC: 6 AN: 60258

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152282 Hom.: 1 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74468

African (AFR) AF: 0.00 AC: 0 AN: 41566

American (AMR) AF: 0.00 AC: 0 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00155 AC: 8 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.000377 AC: 4 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68008

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000982

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	3	3	Glycogen storage disease, type II (6)
-	1	4	not provided (5)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.63
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs144090460; hg19: chr17-78086706;