rs1379595858

chr17-80105007-C-Achr17-80105007-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000152.5(GAA):c.421C>A(p.Leu141Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. L141L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.998

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 Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GAA	NM_000152.5	c.421C>A	p.Leu141Met	missense_variant	2/20	ENST00000302262.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GAA	ENST00000302262.8	c.421C>A	p.Leu141Met	missense_variant	2/20	1	NM_000152.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Glycogen storage disease, type II Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Counsyl

Jan 20, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	21
Dann	Uncertain	0.98
DEOGEN2	Benign	0.017	T;.;T;T
Eigen	Benign	0.045
Eigen_PC	Benign	0.099
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.64	T;T;.;T
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.65	D;D;D;D
MetaSVM	Benign	-0.32	T
MutationTaster	Benign	0.96	N;N
PrimateAI	Benign	0.45	T
Sift4G	Uncertain	0.019	D;D;T;T
Polyphen		0.65	.;.;P;P
Vest4		0.72, 0.72
MutPred		0.76		Gain of methylation at K137 (P = 0.0615);Gain of methylation at K137 (P = 0.0615);Gain of methylation at K137 (P = 0.0615);Gain of methylation at K137 (P = 0.0615);
MVP		0.92
MPC		0.18
ClinPred		0.51	D
GERP RS		4.8
Varity_R		0.22
gMVP		0.44

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

Other links and lift over

dbSNP: rs1379595858; hg19: chr17-78078806;