Variant 4-102632103-T-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005908.4(MANBA):c.2594A>T(p.Glu865Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000822 in 1,460,040 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000082 ( 0 hom. )

Consequence

MANBA
NM_005908.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.55

Variant links:

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANBA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.31038374).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MANBA	NM_005908.4 linkuse as main transcript	c.2594A>T	p.Glu865Val	missense_variant	17/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1 linkuse as main transcript	c.2519A>T	p.Glu840Val	missense_variant	18/18		XP_047271648.1
MANBA	XM_047415693.1 linkuse as main transcript	c.2519A>T	p.Glu840Val	missense_variant	18/18		XP_047271649.1
MANBA	XM_047415694.1 linkuse as main transcript	c.1946A>T	p.Glu649Val	missense_variant	13/13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 linkuse as main transcript	c.2594A>T	p.Glu865Val	missense_variant	17/17		NM_005908.4	ENSP00000495247	P1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000822

AC:

AN:

1460040

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726448

show subpopulations

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:

0.0000108

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 15, 2024

The c.2594A>T (p.E865V) alteration is located in exon 17 (coding exon 17) of the MANBA gene. This alteration results from a A to T substitution at nucleotide position 2594, causing the glutamic acid (E) at amino acid position 865 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Uncertain

0.018

BayesDel_noAF

Benign

-0.21

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.65

D;D;.;.

Eigen

Benign

0.13

Eigen_PC

Benign

0.17

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.87

.;D;D;D

M_CAP

Uncertain

0.092

MetaRNN

Benign

0.31

T;T;T;T

MetaSVM

Benign

-0.39

MutationAssessor

Uncertain

2.9

M;M;.;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.29

PROVEAN

Uncertain

-2.9

D;.;.;D

REVEL

Benign

0.29

Sift

Benign

0.23

T;.;.;T

Sift4G

Benign

0.076

T;.;.;T

Polyphen

0.10

B;B;.;P

Vest4

0.35

MutPred

0.32

Loss of glycosylation at P860 (P = 0.0164);Loss of glycosylation at P860 (P = 0.0164);.;.;

MVP

0.53

MPC

0.23

ClinPred

0.98

GERP RS

4.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.17

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over