rs150536507

Variant names:

• chr17-80117683-G-A
• rs150536507
• NM_000152.5:c.2415G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80117683-G-A
• chr17-80117683-G-T

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Moderate BP6 BP7 BS2_Supporting

The NM_000152.5(GAA):​c.2415G>A​(p.Val805Val) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00152 in 1,612,432 control chromosomes in the GnomAD database, including 2 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. V805V) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0016 (2 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:7
• Conservation: PhyloP100: 2.09
• 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_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 17-80117683-G-A is Benign according to our data. Variant chr17-80117683-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 194697.
• BP7: Synonymous conserved (PhyloP=2.09 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 2 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.2415G>A	p.Val805Val	synonymous	Exon 17 of 20	NP_000143.2
	GAA	NM_001079803.3		c.2415G>A	p.Val805Val	synonymous	Exon 18 of 21	NP_001073271.1
	GAA	NM_001079804.3		c.2415G>A	p.Val805Val	synonymous	Exon 17 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.2415G>A	p.Val805Val	synonymous	Exon 17 of 20	ENSP00000305692.3
	GAA	ENST00000390015.7	TSL:1	c.2415G>A	p.Val805Val	synonymous	Exon 18 of 21	ENSP00000374665.3
	GAA	ENST00000933406.1		c.2430G>A	p.Val810Val	synonymous	Exon 17 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00110 AC: 168 AN: 152182 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00209

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000471

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00163

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.000900 AC: 223 AN: 247888 AF XY: 0.000839

Gnomad AFR exome AF: 0.000189

Gnomad AMR exome AF: 0.00142

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000186

Gnomad NFE exome AF: 0.00143

Gnomad OTH exome AF: 0.00132

GnomAD4 exome AF: 0.00156 AC: 2275 AN: 1460250 Hom.: 2 Cov.: 35 AF XY: 0.00147 AC XY: 1068 AN XY: 726426

African (AFR) AF: 0.000209 AC: 7 AN: 33474

American (AMR) AF: 0.00141 AC: 63 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.0000383 AC: 1 AN: 26108

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.000115 AC: 6 AN: 52124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.00191 AC: 2122 AN: 1111882

Other (OTH) AF: 0.00124 AC: 75 AN: 60350

GnomAD4 genome AF: 0.00110 AC: 168 AN: 152182 Hom.: 0 Cov.: 33 AF XY: 0.00108 AC XY: 80 AN XY: 74348

African (AFR) AF: 0.000410 AC: 17 AN: 41442

American (AMR) AF: 0.00209 AC: 32 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4836

European-Finnish (FIN) AF: 0.000471 AC: 5 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00163 AC: 111 AN: 68024

Other (OTH) AF: 0.00143 AC: 3 AN: 2094

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.00144

EpiCase AF: 0.00136

EpiControl AF: 0.00136

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	3	Glycogen storage disease, type II (6)
-	1	2	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.37
CADD	Benign	9.5
DANN	Benign	0.81
PhyloP100		2.1
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: rs150536507; hg19: chr17-78091482;