17-80108767-G-T

Position:

• chr17-80108767-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_000152.5(GAA):​c.1265G>T​(p.Arg422Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000823 in 1,457,670 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign 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. R422Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000082 (0 hom.)
• Consequence: GAA NM_000152.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.288

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3484708).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GAA	NM_000152.5	c.1265G>T	p.Arg422Leu	missense_variant	8/20	ENST00000302262.8	NP_000143.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GAA	ENST00000302262.8	c.1265G>T	p.Arg422Leu	missense_variant	8/20	1	NM_000152.5	ENSP00000305692.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000823 AC: 12 AN: 1457670 Hom.: 0 Cov.: 36 AF XY: 0.00000828 AC XY: 6 AN XY: 724922

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000990

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.0095	T
BayesDel_noAF	Benign	-0.25
CADD	Benign	5.9
DANN	Benign	0.77
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.073	N
LIST_S2	Benign	0.15	.;T
M_CAP	Uncertain	0.28	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	1.2	L;L
PrimateAI	Benign	0.24	T
PROVEAN	Uncertain	-2.4	N;N
REVEL	Benign	0.28
Sift	Benign	0.28	T;T
Sift4G	Benign	0.27	T;T
Polyphen		0.0	B;B
Vest4		0.30
MutPred		0.58		Loss of disorder (P = 0.0626);Loss of disorder (P = 0.0626);
MVP		0.50
MPC		0.14
ClinPred		0.061	T
GERP RS		-8.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.62

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: rs2229224; hg19: chr17-78082566; COSMIC: COSV100163643; COSMIC: COSV100163643;