rs141017311

Variant names:

• chr17-80113329-G-A
• rs141017311
• NM_000152.5:c.2152G>A

Your query was ambiguous. Multiple possible variants found:

• chr17-80113329-G-A
• chr17-80113329-G-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BS3_Supporting BP4

This summary comes from the ClinGen Evidence Repository: The NM_000152.5:c.2152G>A variant in GAA is a missense variant predicted to cause substitution of valine by isoleucine at amino acid 718 (p.Val718Ile). The highest continental population minor allele frequency in gnomAD v2.1.1 is 0.00011 in the South Asian population, which is lower than the ClinGen Lysosomal Diseases VCEP's threshold (<0.001) for PM2_Supporting. The highest minor allele frequency in any population is 0.005329 in the Ashkenazi Jewish population. This allele frequency meets the criteria for BS1 (>0.005) but BS1 was not applied because the Ashkenazi Jewish population is not defined as a continental population (PMID:30311383). When expressed in COS-7 cells, this variant does not result in significantly reduced GAA activity, and the gene product is normally synthesized and/or processed (PMID 22644586, 31228295) (BS3_Supporting). The computational predictor REVEL gives a score of 0.193 which is below the threshold of 0.5, evidence that does not predict a damaging effect on GAA function. The computational splicing predictor SpliceAI suggests that the variant has no impact on splicing (BP4). There is a ClinVar entry for this variant (Variation ID: 281232) with four submitters classifying the variant as a variant of uncertain significance, four as likely benign and one as benign. In summary, this variant meets the criteria to be classified as likely benign for Pompe disease. GAA-specific ACMG/AMP criteria met, based on the specifications of the ClinGen Lysosomal Diseases VCEP: BP4, BS3_Supporting.(Classification approved by the ClinGen Lysosomal Diseases VCEP on May 21, 2024) LINK:https://erepo.genome.network/evrepo/ui/classification/CA8815626/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Likely benign reviewed by expert panel U:4 B:8
• Conservation: PhyloP100: -1.41
• 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: Likely_benign. The variant received -2 ACMG points.

• BP4: For more information check the summary or visit ClinGen Evidence Repository.
• BS3: For more information check the summary or visit ClinGen Evidence Repository.

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.2152G>A	p.Val718Ile	missense	Exon 15 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2152G>A	p.Val718Ile	missense	Exon 16 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2152G>A	p.Val718Ile	missense	Exon 15 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.2152G>A	p.Val718Ile	missense	Exon 15 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2152G>A	p.Val718Ile	missense	Exon 16 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2167G>A	p.Val723Ile	missense	Exon 15 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.000204 AC: 31 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000274 AC: 60 AN: 219060 AF XY: 0.000262

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00550

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000127 AC: 184 AN: 1443584 Hom.: 0 Cov.: 33 AF XY: 0.000131 AC XY: 94 AN XY: 716036

African (AFR) AF: 0.00 AC: 0 AN: 33198

American (AMR) AF: 0.00 AC: 0 AN: 42740

Ashkenazi Jewish (ASJ) AF: 0.00511 AC: 131 AN: 25658

East Asian (EAS) AF: 0.0000258 AC: 1 AN: 38818

South Asian (SAS) AF: 0.0000720 AC: 6 AN: 83278

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51728

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5736

European-Non Finnish (NFE) AF: 0.0000199 AC: 22 AN: 1102842

Other (OTH) AF: 0.000403 AC: 24 AN: 59586

GnomAD4 genome AF: 0.000204 AC: 31 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74340

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00691 AC: 24 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

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

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68036

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000473 Hom.: 0

Bravo AF: 0.000159

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000182 AC: 22

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	2	4	Glycogen storage disease, type II (6)
-	2	1	not provided (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Hypertrophic cardiomyopathy (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	0.64
DANN	Benign	0.80
DEOGEN2	Uncertain	0.52	D
Eigen	Benign	-1.2
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.044	N
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.18	D
MetaRNN	Benign	0.0076	T
MetaSVM	Benign	-0.64	T
MutationAssessor	Benign	0.99	L
PhyloP100		-1.4
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-0.40	N
REVEL	Benign	0.19
Sift	Benign	0.35	T
Sift4G	Benign	0.56	T
Polyphen		0.0080	B
Vest4		0.11
MVP		0.58
MPC		0.091
ClinPred		0.010	T
GERP RS		-3.1
Varity_R		0.058
gMVP		0.42
Mutation Taster		=96/4	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: rs141017311; hg19: chr17-78087128;