rs143642048

Variant names:

• chr17-80118658-G-A
• rs143642048
• NM_000152.5:c.2652G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80118658-G-A
• chr17-80118658-G-C
• chr17-80118658-G-T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Strong BP6 BP7

The NM_000152.5(GAA):​c.2652G>A​(p.Thr884Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00057 in 1,612,242 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. T884T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00059 (1 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:6
• Conservation: PhyloP100: -1.02
• Publications: 1 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_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-80118658-G-A is Benign according to our data. Variant chr17-80118658-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 289488.
• BP7: Synonymous conserved (PhyloP=-1.02 with no splicing effect.

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.2652G>A	p.Thr884Thr	synonymous	Exon 19 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2652G>A	p.Thr884Thr	synonymous	Exon 20 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2652G>A	p.Thr884Thr	synonymous	Exon 19 of 20	NP_001073272.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000302262.8	TSL:1 MANE Select	c.2652G>A	p.Thr884Thr	synonymous	Exon 19 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2652G>A	p.Thr884Thr	synonymous	Exon 20 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.2667G>A	p.Thr889Thr	synonymous	Exon 19 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00151

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000432 AC: 108 AN: 249892 AF XY: 0.000422

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00138

Gnomad NFE exome AF: 0.000599

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000594 AC: 867 AN: 1459970 Hom.: 1 Cov.: 33 AF XY: 0.000555 AC XY: 403 AN XY: 726308

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44724

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

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

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86246

European-Finnish (FIN) AF: 0.00221 AC: 114 AN: 51546

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

European-Non Finnish (NFE) AF: 0.000638 AC: 710 AN: 1111994

Other (OTH) AF: 0.000513 AC: 31 AN: 60378

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74470

African (AFR) AF: 0.000168 AC: 7 AN: 41546

American (AMR) AF: 0.00 AC: 0 AN: 15306

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00151 AC: 16 AN: 10610

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

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000481 Hom.: 0

Bravo AF: 0.000355

EpiCase AF: 0.000763

EpiControl AF: 0.000533

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	3	Glycogen storage disease, type II (5)
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.4
DANN	Benign	0.42
PhyloP100		-1.0
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143642048; hg19: chr17-78092457; COSMIC: COSV100162891; COSMIC: COSV100162891;