rs139850074

Variant names:

• chr17-80117685-C-T
• rs139850074
• NM_000152.5:c.2417C>T
• GAA p.Thr806Met

Variant summary

Our verdict is Uncertain significance. The variant received -1 ACMG points: 0P and 1B. BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5: c.2417C>T variant in GAA is a missense variant predicted to cause substitution of threonine by methionine at amino acid 806 (p.Thr806Met). To our knowledge, this variant has not been reported in the literature in individuals with Pompe disease, and the results of experimental studies are not available. The highest population minor allele frequency in gnomAD v2.1.1 is 0.001189 (42/35310 alleles) in Latino/Admixed American population. This allele frequency meets neither the PM2 allele frequency threshold (<0.001) nor the BS1 allele frequency threshold (>0.005) specified by the ClinGen Lysosomal Diseases VCEP. The computational predictor REVEL gives a score of 0.435 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. No impact on splicing is predicted by SpliceAI (BP4). There is a ClinVar entry for this variant (Variation ID: 252467). In summary, this variant meets the criteria to be classified as a variant of uncertain significance for Pompe disease due to insufficient evidence. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen Lysosomal Diseases VCEP (Specifications Version 2.0): BP4.(Classification approved by the ClinGen Lysosomal Diseases VCEP on June 20, 2023). LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815734/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00056 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00030 (1 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance reviewed by expert panel U:10 B:2
• Conservation: PhyloP100: 0.491
• Publications: 4 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: G2P, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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: Uncertain_significance. The variant received -1 ACMG points.

• BP4: 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.2417C>T	p.Thr806Met	missense	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2417C>T	p.Thr806Met	missense	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2417C>T	p.Thr806Met	missense	Exon 17 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.2417C>T	p.Thr806Met	missense	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2417C>T	p.Thr806Met	missense	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2432C>T	p.Thr811Met	missense	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000565 AC: 86 AN: 152148 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00321

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000456

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000444 AC: 110 AN: 247782 AF XY: 0.000460

Gnomad AFR exome AF: 0.0000629

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000929

Gnomad NFE exome AF: 0.000459

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000304 AC: 444 AN: 1460242 Hom.: 1 Cov.: 35 AF XY: 0.000300 AC XY: 218 AN XY: 726422

African (AFR) AF: 0.0000597 AC: 2 AN: 33474

American (AMR) AF: 0.000985 AC: 44 AN: 44690

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26104

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.000348 AC: 30 AN: 86230

European-Finnish (FIN) AF: 0.0000767 AC: 4 AN: 52124

Middle Eastern (MID) AF: 0.000529 AC: 3 AN: 5674

European-Non Finnish (NFE) AF: 0.000301 AC: 335 AN: 1111902

Other (OTH) AF: 0.000414 AC: 25 AN: 60348

GnomAD4 genome AF: 0.000565 AC: 86 AN: 152266 Hom.: 0 Cov.: 33 AF XY: 0.000658 AC XY: 49 AN XY: 74454

African (AFR) AF: 0.0000722 AC: 3 AN: 41556

American (AMR) AF: 0.00320 AC: 49 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000622 AC: 3 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000456 AC: 31 AN: 68006

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000349 Hom.: 0

Bravo AF: 0.000688

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000237

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.11
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.71	D
Eigen	Benign	-0.19
Eigen_PC	Benign	-0.22
FATHMM_MKL	Benign	0.049	N
LIST_S2	Benign	0.84	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.12	T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Uncertain	2.0	M
PhyloP100		0.49
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.4	N
REVEL	Uncertain	0.43
Sift	Benign	0.062	T
Sift4G	Benign	0.098	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.086
gMVP		0.46
Mutation Taster		=79/21	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs139850074; hg19: chr17-78091484; COSMIC: COSV100163624; COSMIC: COSV100163624;