NM_000152.5:c.547-4C>G

Variant names:

• chr17-80105745-C-G
• rs3816256
• NM_000152.5:c.547-4C>G

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.547-4C>G in gnomAD v2.1.1 is 0.7403 in the European non-Finnish population. Note that the minor allele frequency is even higher in the Ashkenazi Jewish (0.77927) and European Finnish (0.75914) populations. These allele frequencies are higher than the ClinGen LSD VCEP’s BA1 threshold (>0.01), meeting this criterion. There is a ClinVar entry for this variant (Variation ID: 92485, two star review status), with 6 submitters classifying the variant as 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/CA145784/MONDO:0009290/010

• Frequency:
  • Genomes: 𝑓 0.66 (33579 hom., cov: 32)
  • Exomes 𝑓: 0.71 (372392 hom.)
• Consequence: GAA NM_000152.5 splice_region, intron
• Scores: Splicing: ADA: 0.00004151
• Clinical Significance: Benign reviewed by expert panel U:1 B:15
• Conservation: PhyloP100: -0.139
• Publications: 23 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: PanelApp Australia, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), G2P, 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

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.547-4C>G		splice_region intron	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.547-4C>G		splice_region intron	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.547-4C>G		splice_region intron	N/A	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.547-4C>G		splice_region intron	N/A	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.547-4C>G		splice_region intron	N/A	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.547-4C>G		splice_region intron	N/A	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.657 AC: 99789 AN: 151900 Hom.: 33566 Cov.: 32

Gnomad AFR AF: 0.536

Gnomad AMI AF: 0.649

Gnomad AMR AF: 0.559

Gnomad ASJ AF: 0.770

Gnomad EAS AF: 0.540

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: 0.669 AC: 166767 AN: 249394 AF XY: 0.683

Gnomad AFR exome AF: 0.538

Gnomad AMR exome AF: 0.475

Gnomad ASJ exome AF: 0.780

Gnomad EAS exome AF: 0.529

Gnomad FIN exome AF: 0.759

Gnomad NFE exome AF: 0.740

Gnomad OTH exome AF: 0.720

GnomAD4 exome AF: 0.712 AC: 1037625 AN: 1457634 Hom.: 372392 Cov.: 50 AF XY: 0.713 AC XY: 517028 AN XY: 725362

African (AFR) AF: 0.539 AC: 18025 AN: 33430

American (AMR) AF: 0.489 AC: 21878 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.782 AC: 20433 AN: 26122

East Asian (EAS) AF: 0.560 AC: 22205 AN: 39682

South Asian (SAS) AF: 0.670 AC: 57728 AN: 86214

European-Finnish (FIN) AF: 0.763 AC: 39196 AN: 51352

Middle Eastern (MID) AF: 0.798 AC: 4589 AN: 5750

European-Non Finnish (NFE) AF: 0.730 AC: 810788 AN: 1110078

Other (OTH) AF: 0.710 AC: 42783 AN: 60296

GnomAD4 genome AF: 0.657 AC: 99831 AN: 152018 Hom.: 33579 Cov.: 32 AF XY: 0.654 AC XY: 48619 AN XY: 74298

African (AFR) AF: 0.536 AC: 22194 AN: 41430

American (AMR) AF: 0.558 AC: 8531 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.770 AC: 2672 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2792 AN: 5166

South Asian (SAS) AF: 0.657 AC: 3168 AN: 4824

European-Finnish (FIN) AF: 0.775 AC: 8196 AN: 10572

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

European-Non Finnish (NFE) AF: 0.736 AC: 50030 AN: 67958

Other (OTH) AF: 0.667 AC: 1407 AN: 2110

Alfa AF: 0.707 Hom.: 9153

Bravo AF: 0.638

Asia WGS AF: 0.580 AC: 2020 AN: 3478

EpiCase AF: 0.741

EpiControl AF: 0.741

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: reviewed by expert panel

Pathogenic	VUS	Benign	Condition
-	-	6	Glycogen storage disease, type II (6)
-	-	5	not specified (5)
-	1	3	not provided (4)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	4.6
DANN	Benign	0.53
PhyloP100		-0.14
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000042
dbscSNV1_RF	Benign	0.0
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: rs3816256; hg19: chr17-78079544; COSMIC: COSV56408701; COSMIC: COSV56408701;