rs761221259

Variant names:

• chr17-80104998-C-G
• rs761221259
• NM_000152.5:c.412C>G

Your query was ambiguous. Multiple possible variants found:

• chr17-80104998-C-G
• chr17-80104998-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000152.5(GAA):​c.412C>G​(p.Leu138Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,460,600 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. L138L) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:6
• Conservation: PhyloP100: 0.172
• Publications: 5 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: Uncertain_significance. The variant received 1 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.07983363).

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.412C>G	p.Leu138Val	missense	Exon 2 of 20	NP_000143.2
	GAA	NM_001079803.3		c.412C>G	p.Leu138Val	missense	Exon 3 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.412C>G	p.Leu138Val	missense	Exon 2 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.412C>G	p.Leu138Val	missense	Exon 2 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.412C>G	p.Leu138Val	missense	Exon 3 of 21	ENSP00000374665.3
	GAA	ENST00000570803.6	TSL:5	c.412C>G	p.Leu138Val	missense	Exon 2 of 20	ENSP00000460543.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000161 AC: 4 AN: 248088 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1460600 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 726614

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

American (AMR) AF: 0.0000895 AC: 4 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26130

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52212

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111982

Other (OTH) AF: 0.00 AC: 0 AN: 60384

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	4	-	Glycogen storage disease, type II (4)
-	2	-	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	19
DANN	Benign	0.92
DEOGEN2	Benign	0.0041	T
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.44
FATHMM_MKL	Benign	0.21	N
LIST_S2	Benign	0.68	T
M_CAP	Benign	0.046	D
MetaRNN	Benign	0.080	T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.86	L
PhyloP100		0.17
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.15
Sift	Benign	0.51	T
Sift4G	Uncertain	0.031	D
Polyphen		0.12	B
Vest4		0.11
MutPred		0.32		Gain of methylation at K137 (P = 0.0315)
MVP		0.81
MPC		0.11
ClinPred		0.048	T
GERP RS		3.6
Varity_R		0.14
gMVP		0.42
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs761221259; hg19: chr17-78078797;