rs1800315

Variant names:

• chr17-80118786-C-T
• rs1800315
• NM_000152.5:c.2780C>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.2780C>T (p.Thr927Ile) in gnomAD v2.1.1 is 0.1317 in the African 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: 92482; 2 star review status) with six submitters classifying the variant as benign, and two 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/CA145778/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.042 (363 hom., cov: 32)
  • Exomes 𝑓: 0.010 (484 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign reviewed by expert panel B:14
• Conservation: PhyloP100: 2.32
• Publications: 19 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 -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.2780C>T	p.Thr927Ile	missense	Exon 19 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.2780C>T	p.Thr927Ile	missense	Exon 20 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.2780C>T	p.Thr927Ile	missense	Exon 19 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.2780C>T	p.Thr927Ile	missense	Exon 19 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.2780C>T	p.Thr927Ile	missense	Exon 20 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.2795C>T	p.Thr932Ile	missense	Exon 19 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.0423 AC: 6434 AN: 152174 Hom.: 363 Cov.: 32

Gnomad AFR AF: 0.132

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0160

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000962

Gnomad SAS AF: 0.0511

Gnomad FIN AF: 0.0117

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.00451

Gnomad OTH AF: 0.0258

GnomAD2 exomes AF: 0.0188 AC: 4712 AN: 250594 AF XY: 0.0183

Gnomad AFR exome AF: 0.131

Gnomad AMR exome AF: 0.00660

Gnomad ASJ exome AF: 0.000497

Gnomad EAS exome AF: 0.000653

Gnomad FIN exome AF: 0.0105

Gnomad NFE exome AF: 0.00416

Gnomad OTH exome AF: 0.0116

GnomAD4 exome AF: 0.0103 AC: 15039 AN: 1461080 Hom.: 484 Cov.: 33 AF XY: 0.0110 AC XY: 7984 AN XY: 726834

African (AFR) AF: 0.134 AC: 4487 AN: 33480

American (AMR) AF: 0.00751 AC: 336 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000574 AC: 15 AN: 26136

East Asian (EAS) AF: 0.000504 AC: 20 AN: 39700

South Asian (SAS) AF: 0.0482 AC: 4157 AN: 86258

European-Finnish (FIN) AF: 0.0101 AC: 533 AN: 52628

Middle Eastern (MID) AF: 0.0109 AC: 63 AN: 5768

European-Non Finnish (NFE) AF: 0.00406 AC: 4514 AN: 1112000

Other (OTH) AF: 0.0151 AC: 914 AN: 60386

GnomAD4 genome AF: 0.0423 AC: 6448 AN: 152292 Hom.: 363 Cov.: 32 AF XY: 0.0420 AC XY: 3130 AN XY: 74478

African (AFR) AF: 0.131 AC: 5459 AN: 41550

American (AMR) AF: 0.0159 AC: 244 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.000965 AC: 5 AN: 5184

South Asian (SAS) AF: 0.0519 AC: 250 AN: 4814

European-Finnish (FIN) AF: 0.0117 AC: 124 AN: 10628

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.00451 AC: 307 AN: 68028

Other (OTH) AF: 0.0260 AC: 55 AN: 2114

Alfa AF: 0.0161 Hom.: 424

Bravo AF: 0.0447

TwinsUK AF: 0.00566 AC: 21

ALSPAC AF: 0.00467 AC: 18

ESP6500AA AF: 0.132 AC: 582

ESP6500EA AF: 0.00349 AC: 30

ExAC AF: 0.0219 AC: 2661

Asia WGS AF: 0.0340 AC: 119 AN: 3478

EpiCase AF: 0.00398

EpiControl AF: 0.00320

ClinVar

ClinVar submissions

Significance: Benign

Revision: reviewed by expert panel

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.72	D
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Pathogenic	3.0	M
PhyloP100		2.3
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-3.1	D
REVEL	Uncertain	0.48
Sift	Benign	0.040	D
Sift4G	Benign	0.086	T
Polyphen		0.95	P
Vest4		0.050
MPC		0.13
ClinPred		0.024	T
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.19
gMVP		0.64
Mutation Taster		=85/15	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

Other links and lift over

dbSNP: rs1800315; hg19: chr17-78092585; COSMIC: COSV56408041; COSMIC: COSV56408041;