17-80112653-C-T

Variant names:

• chr17-80112653-C-T
• rs61736896
• NM_000152.5:c.1830C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Very_Strong BP7 BS2_Supporting

The NM_000152.5(GAA):​c.1830C>T​(p.Ala610Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000985 in 1,612,782 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. A610A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00097 (7 hom.)
• Consequence: GAA NM_000152.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -3.45
• Publications: 5 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: Genomics England PanelApp, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 17-80112653-C-T is Benign according to our data. Variant chr17-80112653-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255356.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-3.45 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 7 AR geneVariant has number of homozygotes lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

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.1830C>T	p.Ala610Ala	synonymous	Exon 13 of 20	NP_000143.2	P10253
	GAA	NM_001079803.3		c.1830C>T	p.Ala610Ala	synonymous	Exon 14 of 21	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.1830C>T	p.Ala610Ala	synonymous	Exon 13 of 20	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.1830C>T	p.Ala610Ala	synonymous	Exon 13 of 20	ENSP00000305692.3	P10253
	GAA	ENST00000390015.7	TSL:1	c.1830C>T	p.Ala610Ala	synonymous	Exon 14 of 21	ENSP00000374665.3	P10253
	GAA	ENST00000933406.1		c.1845C>T	p.Ala615Ala	synonymous	Exon 13 of 20	ENSP00000603465.1

Frequencies

GnomAD3 genomes AF: 0.00114 AC: 174 AN: 152228 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00282

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00184

Gnomad OTH AF: 0.000955

GnomAD2 exomes AF: 0.00132 AC: 324 AN: 246008 AF XY: 0.00132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000350

Gnomad ASJ exome AF: 0.00303

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00293

Gnomad NFE exome AF: 0.00179

Gnomad OTH exome AF: 0.00166

GnomAD4 exome AF: 0.000968 AC: 1414 AN: 1460436 Hom.: 7 Cov.: 33 AF XY: 0.00103 AC XY: 746 AN XY: 726532

African (AFR) AF: 0.0000299 AC: 1 AN: 33470

American (AMR) AF: 0.000515 AC: 23 AN: 44682

Ashkenazi Jewish (ASJ) AF: 0.00260 AC: 68 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39684

South Asian (SAS) AF: 0.000603 AC: 52 AN: 86208

European-Finnish (FIN) AF: 0.00262 AC: 137 AN: 52304

Middle Eastern (MID) AF: 0.000867 AC: 5 AN: 5766

European-Non Finnish (NFE) AF: 0.000960 AC: 1067 AN: 1111864

Other (OTH) AF: 0.00101 AC: 61 AN: 60352

GnomAD4 genome AF: 0.00114 AC: 174 AN: 152346 Hom.: 1 Cov.: 33 AF XY: 0.00113 AC XY: 84 AN XY: 74482

African (AFR) AF: 0.000192 AC: 8 AN: 41572

American (AMR) AF: 0.000261 AC: 4 AN: 15314

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000414 AC: 2 AN: 4830

European-Finnish (FIN) AF: 0.00282 AC: 30 AN: 10632

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00184 AC: 125 AN: 68028

Other (OTH) AF: 0.000945 AC: 2 AN: 2116

Alfa AF: 0.00167 Hom.: 1

Bravo AF: 0.000763

EpiCase AF: 0.00153

EpiControl AF: 0.000890

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	3	Glycogen storage disease, type II (3)
-	-	2	not provided (2)
-	-	1	Cardiovascular phenotype (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	3.1
DANN	Benign	0.81
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs61736896; hg19: chr17-78086452; COSMIC: COSV56407812; COSMIC: COSV56407812;