Genetic Variant GAA:p.Pro285Leu (chr17-80107718-C-T) – ACMG Classification: Likely_pathogenic (9 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1PM2PM5PP2PP3_Moderate

The NM_000152.5(GAA):c.854C>T(p.Pro285Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000719 in 1,389,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P285S) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

GAA
NM_000152.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.79

Variant links:

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 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

PM1

In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 10 uncertain in NM_000152.5

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-80107717-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 281052.Status of the report is reviewed_by_expert_panel, 3 stars.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 201 curated pathogenic missense variants (we use a threshold of 10). The gene has 50 curated benign missense variants. Gene score misZ: -0.63308 (below the threshold of 3.09). Trascript score misZ: -0.32889 (below the threshold of 3.09). GenCC associations: The gene is linked to glycogen storage disease II, glycogen storage disease due to acid maltase deficiency, late-onset, glycogen storage disease due to acid maltase deficiency, infantile onset.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.937

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GAA	NM_000152.5 link	c.854C>T	p.Pro285Leu	missense_variant	Exon 4 of 20	ENST00000302262.8	NP_000143.2	P10253

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8 link	c.854C>T	p.Pro285Leu	missense_variant	Exon 4 of 20	1	NM_000152.5	ENSP00000305692.3		P10253

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000511

AC:

AN:

195744

AF XY:

0.00000941

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000115

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

7.19e-7

AC:

AN:

1389866

Hom.:

Cov.:

AF XY:

0.00000145

AC XY:

AN XY:

688728

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32162

American (AMR)

AF:

0.00

AC:

AN:

41122

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23616

East Asian (EAS)

AF:

0.00

AC:

AN:

38508

South Asian (SAS)

AF:

0.00

AC:

AN:

81030

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49034

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5362

European-Non Finnish (NFE)

AF:

9.42e-7

AC:

AN:

1062114

Other (OTH)

AF:

0.00

AC:

AN:

56918

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000825

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.53

BayesDel_addAF

Pathogenic

0.33

BayesDel_noAF

Pathogenic

0.24

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.93

D;D

Eigen

Uncertain

0.64

Eigen_PC

Uncertain

0.51

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;D

M_CAP

Pathogenic

0.30

MetaRNN

Pathogenic

0.94

D;D

MetaSVM

Uncertain

0.70

MutationAssessor

Pathogenic

3.0

M;M

PhyloP100

7.8

PrimateAI

Uncertain

0.60

PROVEAN

Pathogenic

-9.3

D;D

REVEL

Pathogenic

0.74

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0020

D;D

Polyphen

1.0

D;D

Vest4

0.95

MutPred

0.54

Loss of disorder (P = 0.0607);Loss of disorder (P = 0.0607);

MVP

1.0

MPC

0.54

ClinPred

1.0

GERP RS

5.1

Varity_R

0.91

gMVP

0.88

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

Publications

LitVar

Below is the list of publications found by LitVar for variant 17:80107718 C>T . It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over