17-80101562-C-T

Variant names:

• chr17-80101562-C-T
• rs544259653
• ENST00000570803.6:c.-96C>T

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The ENST00000714061.1(GAA):​n.-176C>T variant causes a non coding transcript exon change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00263 in 150,842 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency: Genomes: 𝑓 0.0026 (3 hom., cov: 33)
• Consequence: GAA ENST00000714061.1 non_coding_transcript_exon
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.950
• Publications: 1 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 17-80101562-C-T is Benign according to our data. Variant chr17-80101562-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1342753.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00263 (397/150842) while in subpopulation AFR AF = 0.00935 (387/41402). AF 95% confidence interval is 0.00858. There are 3 homozygotes in GnomAd4. There are 175 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000714061.1. 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.-361C>T		upstream_gene	N/A	NP_000143.2	P10253
	GAA	NM_001079803.3		c.-176C>T		upstream_gene	N/A	NP_001073271.1	P10253
	GAA	NM_001079804.3		c.-96C>T		upstream_gene	N/A	NP_001073272.1	P10253

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAA	ENST00000570803.6	TSL:5	c.-96C>T		5_prime_UTR	Exon 1 of 20	ENSP00000460543.2	P10253
	GAA	ENST00000714061.1		n.-176C>T		non_coding_transcript_exon	Exon 1 of 21	ENSP00000519351.1	A0AAQ5BHG9
	GAA	ENST00000714061.1		n.-176C>T		5_prime_UTR	Exon 1 of 21	ENSP00000519351.1	A0AAQ5BHG9

Frequencies

GnomAD3 genomes AF: 0.00262 AC: 395 AN: 150734 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00933

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000462

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00145

GnomAD4 exome Cov.: 0

GnomAD4 genome AF: 0.00263 AC: 397 AN: 150842 Hom.: 3 Cov.: 33 AF XY: 0.00237 AC XY: 175 AN XY: 73692

African (AFR) AF: 0.00935 AC: 387 AN: 41402

American (AMR) AF: 0.000462 AC: 7 AN: 15156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3452

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10060

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67478

Other (OTH) AF: 0.00144 AC: 3 AN: 2090

Alfa AF: 0.00185 Hom.: 0

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	7.1
DANN	Benign	0.95
PhyloP100		-0.95
PromoterAI		0.016	Neutral

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs544259653; hg19: chr17-78075361;