rs1042395

Variant names:

• chr17-80105870-G-A
• rs1042395
• NM_000152.5:c.668G>A
• GAA p.Arg223His

Your query was ambiguous. Multiple possible variants found:

• chr17-80105870-G-A
• chr17-80105870-G-C
• chr17-80105870-G-T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BA1

This summary comes from the ClinGen Evidence Repository: The highest continental population minor allele frequency for c.668G>A (p.Arg223His) in gnomAD v2.1.1 is 0.74034 in the European non-Finnish population. This is higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), therefore meeting the BA1 criterion. There is a ClinVar entry for this variant (Variation ID: 92488; 2 star review status) with six submitters classifying the variant as benign, and one as likely benign. In summary, this variant meets the criteria to be classified as benign for Pompe disease. GAA-specific ACMG/AMP criteria applied, as specified by the ClinGen LSD VCEP: BA1. LINK:https://erepo.genome.network/evrepo/ui/classification/CA145791/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.66 (33595 hom., cov: 33)
  • Exomes 𝑓: 0.71 (369171 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign reviewed by expert panel U:1 B:16
• Conservation: PhyloP100: -0.0360
• Publications: 61 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: G2P, ClinGen, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• 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 -8 ACMG points.

• BA1: 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.668G>A	p.Arg223His	missense	Exon 3 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.668G>A	p.Arg223His	missense	Exon 4 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.668G>A	p.Arg223His	missense	Exon 3 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.668G>A	p.Arg223His	missense	Exon 3 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.668G>A	p.Arg223His	missense	Exon 4 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.668G>A	p.Arg223His	missense	Exon 3 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99833 AN: 151982 Hom.: 33582 Cov.: 33

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.658

Gnomad FIN AF: 0.775

Gnomad MID AF: 0.839

Gnomad NFE AF: 0.736

Gnomad OTH AF: 0.667

GnomAD2 exomes AF: 0.666 AC: 162329 AN: 243594 AF XY: 0.681

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.474

Gnomad ASJ exome AF: 0.779

Gnomad EAS exome AF: 0.528

Gnomad FIN exome AF: 0.752

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.711 AC: 1030164 AN: 1448490 Hom.: 369171 Cov.: 58 AF XY: 0.712 AC XY: 512807 AN XY: 720028

African (AFR) AF: 0.539 AC: 17981 AN: 33368

American (AMR) AF: 0.489 AC: 21802 AN: 44582

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20386 AN: 26068

East Asian (EAS) AF: 0.559 AC: 22109 AN: 39564

South Asian (SAS) AF: 0.670 AC: 57680 AN: 86142

European-Finnish (FIN) AF: 0.760 AC: 34338 AN: 45174

Middle Eastern (MID) AF: 0.794 AC: 4121 AN: 5188

European-Non Finnish (NFE) AF: 0.730 AC: 809122 AN: 1108302

Other (OTH) AF: 0.709 AC: 42625 AN: 60102

GnomAD4 genome AF: 0.657 AC: 99875 AN: 152100 Hom.: 33595 Cov.: 33 AF XY: 0.654 AC XY: 48653 AN XY: 74362

African (AFR) AF: 0.536 AC: 22228 AN: 41480

American (AMR) AF: 0.558 AC: 8525 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2671 AN: 3468

East Asian (EAS) AF: 0.539 AC: 2787 AN: 5174

South Asian (SAS) AF: 0.657 AC: 3162 AN: 4814

European-Finnish (FIN) AF: 0.775 AC: 8213 AN: 10594

Middle Eastern (MID) AF: 0.847 AC: 249 AN: 294

European-Non Finnish (NFE) AF: 0.736 AC: 50039 AN: 67972

Other (OTH) AF: 0.667 AC: 1409 AN: 2112

Alfa AF: 0.694 Hom.: 88041

Bravo AF: 0.637

Asia WGS AF: 0.580 AC: 2021 AN: 3476

EpiCase AF: 0.742

EpiControl AF: 0.742

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	7	Glycogen storage disease, type II (7)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.063
BayesDel_addAF	Benign	-0.39	T
BayesDel_noAF	Benign	-0.19
CADD	Benign	17
DANN	Benign	0.80
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.66	T
MetaRNN	Benign	0.000017	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Pathogenic	3.3	M
PhyloP100		-0.036
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.6	N
REVEL	Uncertain	0.39
Sift	Benign	0.54	T
Sift4G	Benign	0.29	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.23
gMVP		0.69
Mutation Taster		=55/45	polymorphism (auto)

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs1042395;

hg19: chr17-78079669;

COSMIC: COSV56406846;

COSMIC: COSV56406846;