NM_000152.5:c.2478G>A

Variant names:

• chr17-80117746-G-A
• rs201183207
• NM_000152.5:c.2478G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2_Supporting

The NM_000152.5(GAA):​c.2478G>A​(p.Leu826Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000198 in 1,608,308 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. L826L) has been classified as Likely benign. The gene GAA is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00018 (3 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 2.93
• Publications: 3 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

Specifications for GAA are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 17-80117746-G-A is Benign according to our data. Variant chr17-80117746-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 285676.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.93 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000414 (63/152320) while in subpopulation EAS AF = 0.0118 (61/5182). AF 95% confidence interval is 0.00941. There are 0 homozygotes in GnomAd4. There are 38 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.2478G>A	p.Leu826Leu	synonymous	Exon 17 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2478G>A	p.Leu826Leu	synonymous	Exon 18 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2478G>A	p.Leu826Leu	synonymous	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.2478G>A	p.Leu826Leu	synonymous	Exon 17 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2478G>A	p.Leu826Leu	synonymous	Exon 18 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2493G>A	p.Leu831Leu	synonymous	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000427 AC: 65 AN: 152202 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0121

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000945 AC: 222 AN: 234994 AF XY: 0.000866

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000300

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0123

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000959

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000175 AC: 255 AN: 1455988 Hom.: 3 Cov.: 34 AF XY: 0.000171 AC XY: 124 AN XY: 724132

African (AFR) AF: 0.00 AC: 0 AN: 33448

American (AMR) AF: 0.00 AC: 0 AN: 44022

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25948

East Asian (EAS) AF: 0.00565 AC: 224 AN: 39628

South Asian (SAS) AF: 0.0000699 AC: 6 AN: 85778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50996

Middle Eastern (MID) AF: 0.000183 AC: 1 AN: 5456

European-Non Finnish (NFE) AF: 0.00000540 AC: 6 AN: 1110520

Other (OTH) AF: 0.000299 AC: 18 AN: 60192

GnomAD4 genome AF: 0.000414 AC: 63 AN: 152320 Hom.: 0 Cov.: 33 AF XY: 0.000510 AC XY: 38 AN XY: 74484

African (AFR) AF: 0.00 AC: 0 AN: 41564

American (AMR) AF: 0.0000654 AC: 1 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0118 AC: 61 AN: 5182

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68024

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000434

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	5.9
DANN	Benign	0.71
PhyloP100		2.9
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)		0.0		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: rs201183207; hg19: chr17-78091545; COSMIC: COSV107393404; COSMIC: COSV107393404;