rs144090460

Variant names:

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

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4 BP7

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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5	c.1920T>G	p.Pro640Pro	synonymous_variant	Exon 14 of 20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1920T>G	p.Pro640Pro	synonymous_variant	Exon 14 of 20	1	NM_000152.5	ENSP00000305692.3

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

GnomAD3 exomes AF: 0.000181 AC: 44 AN: 242468 Hom.: 0 AF XY: 0.000152 AC XY: 20 AN XY: 132012

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 SAS exome AF: 0.0000337

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000555

Gnomad4 SAS exome AF: 0.0000585

Gnomad4 FIN exome AF: 0.000496

Gnomad4 NFE exome AF: 0.0000810

Gnomad4 OTH exome AF: 0.0000996

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

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.000123 Hom.: 0

Bravo AF: 0.0000982

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:4 Benign:9

Revision: reviewed by expert panel

Submissions by phenotype

Glycogen storage disease, type II Uncertain:3 Benign:3

Apr 28, 2017

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Jan 15, 2020

Natera, Inc.

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jul 22, 2021

Genome-Nilou Lab

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 22, 2020

Broad Center for Mendelian Genomics, Broad Institute of MIT and Harvard

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: curation

The c.1920T>G (p.Pro640=) variant in GAA has not been reported in individuals with Glycogen Storage Disease II but has been reported in 2 European individuals with unexplained limb-girdle muscle weakness (PMID: 29149851). This variant has also been reported likely benign (by GeneDx, PreventionGenetics, Mayo Clinic Genetic Testing Laboratories, and Invitae) and as a VUS by EGL in ClinVar (Variation ID: 255358). This variant has been identified in 0.09150% (18/19672) of East Asian chromosomes, 0.04553% (11/24162) of European (Finnish) chromosomes, and 0.01683% (21/124752) of European (non-Finnish) chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs144090460). Although this variant has been seen in the general population, its frequency is low enough to be consistent with a recessive carrier frequency. Computational prediction tools and conservation analyses suggest that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. However, novel synonymous variants supported by computational evidence without raised suspicion for an impact are likely benign (Richards 2015). In summary, although additional studies are required to fully establish its clinical significance, this variant is likely benign. ACMG/AMP Criteria applied: PM2, BP4, BP7 (Richards 2015). -

May 07, 2024

ClinGen Lysosomal Storage Disorder Variant Curation Expert Panel

Significance: Likely benign

Review Status: reviewed by expert panel

Collection Method: curation

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). -

not provided Uncertain:1 Benign:4

Nov 11, 2015

Eurofins Ntd Llc (ga)

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 01, 2024

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GAA: BP4, BP7 -

May 10, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Sep 14, 2021

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 24444888, 18458862) -

Nov 20, 2023

Revvity Omics, Revvity

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Cardiovascular phenotype Benign:1

Aug 03, 2022

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.71
CADD	Benign	8.3
DANN	Benign	0.63
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs144090460; hg19: chr17-78086706;