rs2866413

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005908.4(MANBA):c.2102C>T(p.Thr701Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,608,224 control chromosomes in the GnomAD database, including 223,306 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.55 ( 23376 hom., cov: 33)

Exomes 𝑓: 0.52 ( 199930 hom. )

Consequence

MANBA
NM_005908.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 1.82

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:

MANBA (HGNC:):

MANBA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=4.2311553E-6).

BP6

Variant 4-102635920-G-A is Benign according to our data. Variant chr4-102635920-G-A is described in ClinVar as [Benign]. Clinvar id is 95319.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102635920-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.624 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4 linkuse as main transcript	c.2102C>T	p.Thr701Met	missense_variant	15/17	ENST00000647097.2	NP_005899.3	O00462
MANBA	XM_047415692.1 linkuse as main transcript	c.2027C>T	p.Thr676Met	missense_variant	16/18		XP_047271648.1
MANBA	XM_047415693.1 linkuse as main transcript	c.2027C>T	p.Thr676Met	missense_variant	16/18		XP_047271649.1
MANBA	XM_047415694.1 linkuse as main transcript	c.1454C>T	p.Thr485Met	missense_variant	11/13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 linkuse as main transcript	c.2102C>T	p.Thr701Met	missense_variant	15/17		NM_005908.4	ENSP00000495247.1		O00462

Frequencies

GnomAD3 genomes

AF:

0.549

AC:

83451

AN:

151906

Hom.:

23342

Cov.:

show subpopulations

Gnomad AFR

AF:

0.630

Gnomad AMI

AF:

0.575

Gnomad AMR

AF:

0.618

Gnomad ASJ

AF:

0.508

Gnomad EAS

AF:

0.515

Gnomad SAS

AF:

0.452

Gnomad FIN

AF:

0.472

Gnomad MID

AF:

0.608

Gnomad NFE

AF:

0.508

Gnomad OTH

AF:

0.556

GnomAD3 exomes

AF:

0.541

AC:

135812

AN:

251266

Hom.:

37895

AF XY:

0.529

AC XY:

71840

AN XY:

135812

show subpopulations

Gnomad AFR exome

AF:

0.635

Gnomad AMR exome

AF:

0.735

Gnomad ASJ exome

AF:

0.492

Gnomad EAS exome

AF:

0.527

Gnomad SAS exome

AF:

0.456

Gnomad FIN exome

AF:

0.487

Gnomad NFE exome

AF:

0.508

Gnomad OTH exome

AF:

0.533

GnomAD4 exome

AF:

0.521

AC:

758213

AN:

1456200

Hom.:

199930

Cov.:

AF XY:

0.517

AC XY:

375007

AN XY:

724730

show subpopulations

Gnomad4 AFR exome

AF:

0.634

Gnomad4 AMR exome

AF:

0.724

Gnomad4 ASJ exome

AF:

0.493

Gnomad4 EAS exome

AF:

0.491

Gnomad4 SAS exome

AF:

0.461

Gnomad4 FIN exome

AF:

0.476

Gnomad4 NFE exome

AF:

0.517

Gnomad4 OTH exome

AF:

0.532

GnomAD4 genome

AF:

0.549

AC:

83529

AN:

152024

Hom.:

23376

Cov.:

AF XY:

0.548

AC XY:

40747

AN XY:

74294

show subpopulations

Gnomad4 AFR

AF:

0.630

Gnomad4 AMR

AF:

0.618

Gnomad4 ASJ

AF:

0.508

Gnomad4 EAS

AF:

0.515

Gnomad4 SAS

AF:

0.452

Gnomad4 FIN

AF:

0.472

Gnomad4 NFE

AF:

0.508

Gnomad4 OTH

AF:

0.549

Alfa

AF:

0.510

Hom.:

45346

Bravo

AF:

0.567

TwinsUK

AF:

0.513

AC:

1903

ALSPAC

AF:

0.520

AC:

2005

ESP6500AA

AF:

0.617

AC:

2720

ESP6500EA

AF:

0.513

AC:

4413

ExAC

AF:

0.533

AC:

64658

Asia WGS

AF:

0.503

AC:

1744

AN:

3478

EpiCase

AF:

0.515

EpiControl

AF:

0.504

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Mar 21, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Mar 29, 2016	Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jan 16, 2013	- -

not provided

Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 13, 2018	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -

Beta-D-mannosidosis

Benign:3

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.70

BayesDel_noAF

Benign

-0.64

CADD

Benign

5.5

DANN

Benign

0.91

DEOGEN2

Benign

0.26

.;T;T;.;.

Eigen

Benign

-1.0

Eigen_PC

Benign

-0.98

FATHMM_MKL

Benign

0.016

LIST_S2

Benign

0.39

T;.;T;T;T

MetaRNN

Benign

0.0000042

T;T;T;T;T

MetaSVM

Benign

-0.95

MutationAssessor

Benign

-0.030

.;N;N;.;.

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.48

.;N;.;.;N

REVEL

Benign

0.042

Sift

Benign

0.17

.;T;.;.;T

Sift4G

Benign

0.12

.;T;.;.;T

Polyphen

0.060, 0.054

.;B;B;.;B

Vest4

0.066, 0.030

MPC

0.078

ClinPred

0.010

GERP RS

2.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.017

gMVP

0.34

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over