rs2172397

Positions:

• chr3-81594016-T-A
• chr3-81594016-T-C
• chr3-81594016-T-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_000158.4(GBE1):​c.1000A>T​(p.Ile334Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts 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. I334V) has been classified as Benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: GBE1 NM_000158.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.82

Genes affected

GBE1 (HGNC:4180): (1,4-alpha-glucan branching enzyme 1) The protein encoded by this gene is a glycogen branching enzyme that catalyzes the transfer of alpha-1,4-linked glucosyl units from the outer end of a glycogen chain to an alpha-1,6 position on the same or a neighboring glycogen chain. Branching of the chains is essential to increase the solubility of the glycogen molecule and, consequently, in reducing the osmotic pressure within cells. Highest level of this enzyme are found in liver and muscle. Mutations in this gene are associated with glycogen storage disease IV (also known as Andersen's disease). [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_000158.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38748276).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GBE1	NM_000158.4	c.1000A>T	p.Ile334Phe	missense_variant	8/16	ENST00000429644.7
GBE1	XR_007095662.1	n.1128A>T		non_coding_transcript_exon_variant	8/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GBE1	ENST00000429644.7	c.1000A>T	p.Ile334Phe	missense_variant	8/16	1	NM_000158.4	P1
GBE1	ENST00000489715.1	c.877A>T	p.Ile293Phe	missense_variant	8/16	2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1353958 Hom.: 0 Cov.: 20 AF XY: 0.00 AC XY: 0 AN XY: 672926

Gnomad4 AFR exome AF: 0.00

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.82
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	D;T
Eigen	Benign	-0.098
Eigen_PC	Benign	0.034
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.37	D
MetaRNN	Benign	0.39	T;T
MetaSVM	Uncertain	-0.059	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	0.87	N;N
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.6	D;D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0010	D;D
Polyphen		0.17	B;B
Vest4		0.39
MutPred		0.68		Loss of catalytic residue at L339 (P = 0.0613);.;
MVP		0.83
MPC		0.061
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.74
gMVP		0.92

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: rs2172397; hg19: chr3-81643167;