rs138034915

chr17-80104954-G-Achr17-80104954-G-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000152.5(GAA):c.368G>A(p.Gly123Glu) variant causes a missense change. The variant allele was found at a frequency of 0.000448 in 1,612,446 control chromosomes in the GnomAD database, including 11 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G123V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00034 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (11 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 4.66

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009648085).
• BP6: Variant 17-80104954-G-A is Benign according to our data. Variant chr17-80104954-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 283495.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.368G>A	p.Gly123Glu	missense_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.368G>A	p.Gly123Glu	missense_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes AF: 0.000342 AC: 52 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000434

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00642

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000989 AC: 245 AN: 247744 Hom.: 5 AF XY: 0.00122 AC XY: 165 AN XY: 134736

Gnomad AFR exome AF: 0.000442

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00769

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000330

GnomAD4 exome AF: 0.000460 AC: 671 AN: 1460128 Hom.: 11 Cov.: 36 AF XY: 0.000631 AC XY: 458 AN XY: 726356

Gnomad4 AFR exome AF: 0.000269

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00684

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000809

Gnomad4 OTH exome AF: 0.00101

GnomAD4 genome AF: 0.000341 AC: 52 AN: 152318 Hom.: 0 Cov.: 33 AF XY: 0.000362 AC XY: 27 AN XY: 74492

Gnomad4 AFR AF: 0.000433

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000201 Hom.: 0

Bravo AF: 0.000234

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00118 AC: 143

Asia WGS AF: 0.00924 AC: 32 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 30, 2020	Variant summary: GAA c.368G>A (p.Gly123Glu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00099 in 247744 control chromosomes, predominantly at a frequency of 0.0077 within the South Asian subpopulation in the gnomAD database, including 5 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in GAA causing Glycogen Storage Disease, Type 2 (Pompe Disease) phenotype (0.0042), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. To our knowledge, no occurrence of c.368G>A in individuals affected with Glycogen Storage Disease, Type 2 (Pompe Disease) and no experimental evidence demonstrating its impact on protein function have been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 07, 2015	- -

Glycogen storage disease, type II Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jul 13, 2020

- -

Primary dilated cardiomyopathy Benign:1

Benign, criteria provided, single submitter

clinical testing

Center for Advanced Laboratory Medicine, UC San Diego Health, University of California San Diego

Jan 05, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.25
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D;.;D;D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T;T;.;T
MetaRNN	Benign	0.0096	T;T;T;T
MetaSVM	Benign	-0.58	T
MutationTaster	Benign	0.93	D;D
PrimateAI	Uncertain	0.49	T
Sift4G	Benign	0.085	T;T;T;T
Polyphen		0.86	.;.;P;P
Vest4		0.24
MVP		0.80
MPC		0.28
ClinPred		0.031	T
GERP RS		4.8
Varity_R		0.47
gMVP		0.70

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs138034915; hg19: chr17-78078753;