17-80116996-G-A

Variant names:

• chr17-80116996-G-A
• rs752122499
• NM_000152.5:c.2218G>A

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_000152.5(GAA):​c.2218G>A​(p.Val740Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,440 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V740L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:4
• Conservation: PhyloP100: 1.20
• 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, 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM1: In a hotspot region, there are 8 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 16 uncertain in NM_000152.5
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease due to acid maltase deficiency, infantile onset, glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.871

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	NM_000152.5	MANE Select	c.2218G>A	p.Val740Met	missense	Exon 16 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2218G>A	p.Val740Met	missense	Exon 17 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2218G>A	p.Val740Met	missense	Exon 16 of 20	NP_001073272.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2218G>A	p.Val740Met	missense	Exon 16 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2218G>A	p.Val740Met	missense	Exon 17 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.2233G>A	p.Val745Met	missense	Exon 16 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000399 AC: 1 AN: 250940 AF XY: 0.00000737

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000883

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461440 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727034

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60390

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	3	-	Glycogen storage disease, type II (3)
-	1	-	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.099	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.77	D
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Benign	0.71	D
LIST_S2	Benign	0.75	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.87	D
MetaSVM	Uncertain	0.49	D
MutationAssessor	Benign	2.0	M
PhyloP100		1.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.56
Sift	Uncertain	0.013	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.92	P
Vest4		0.61
MutPred		0.68		Gain of disorder (P = 0.0789)
MVP		0.98
MPC		0.45
ClinPred		0.79	D
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.32
gMVP		0.65

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: rs752122499; hg19: chr17-78090795;