NM_005908.4:c.757G>A

Variant names:

Variant summary

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

The NM_005908.4(MANBA):c.757G>A(p.Val253Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 1,608,542 control chromosomes in the GnomAD database, including 177,288 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 Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V253L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.40 ( 13451 hom., cov: 30)

Exomes 𝑓: 0.47 ( 163837 hom. )

Consequence

MANBA
NM_005908.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -0.114

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 Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.2812018E-4).

BP6

Variant 4-102690688-C-T is Benign according to our data. Variant chr4-102690688-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 347096.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-102690688-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.485 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4 link	c.757G>A	p.Val253Ile	missense_variant	Exon 6 of 17	ENST00000647097.2	NP_005899.3	O00462
MANBA	XM_047415692.1 link	c.682G>A	p.Val228Ile	missense_variant	Exon 7 of 18		XP_047271648.1
MANBA	XM_047415693.1 link	c.682G>A	p.Val228Ile	missense_variant	Exon 7 of 18		XP_047271649.1
MANBA	XM_047415694.1 link	c.109G>A	p.Val37Ile	missense_variant	Exon 2 of 13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 link	c.757G>A	p.Val253Ile	missense_variant	Exon 6 of 17		NM_005908.4	ENSP00000495247.1		O00462

Frequencies

GnomAD3 genomes

AF:

0.397

AC:

60244

AN:

151564

Hom.:

13440

Cov.:

show subpopulations

Gnomad AFR

AF:

0.193

Gnomad AMI

AF:

0.431

Gnomad AMR

AF:

0.358

Gnomad ASJ

AF:

0.454

Gnomad EAS

AF:

0.463

Gnomad SAS

AF:

0.501

Gnomad FIN

AF:

0.566

Gnomad MID

AF:

0.351

Gnomad NFE

AF:

0.489

Gnomad OTH

AF:

0.387

GnomAD3 exomes

AF:

0.442

AC:

110738

AN:

250716

Hom.:

25805

AF XY:

0.453

AC XY:

61456

AN XY:

135530

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.300

Gnomad ASJ exome

AF:

0.473

Gnomad EAS exome

AF:

0.440

Gnomad SAS exome

AF:

0.493

Gnomad FIN exome

AF:

0.552

Gnomad NFE exome

AF:

0.484

Gnomad OTH exome

AF:

0.444

GnomAD4 exome

AF:

0.469

AC:

683469

AN:

1456860

Hom.:

163837

Cov.:

AF XY:

0.471

AC XY:

341743

AN XY:

724962

show subpopulations

Gnomad4 AFR exome

AF:

0.183

Gnomad4 AMR exome

AF:

0.302

Gnomad4 ASJ exome

AF:

0.472

Gnomad4 EAS exome

AF:

0.503

Gnomad4 SAS exome

AF:

0.492

Gnomad4 FIN exome

AF:

0.556

Gnomad4 NFE exome

AF:

0.479

Gnomad4 OTH exome

AF:

0.447

GnomAD4 genome

AF:

0.397

AC:

60267

AN:

151682

Hom.:

13451

Cov.:

AF XY:

0.399

AC XY:

29595

AN XY:

74092

show subpopulations

Gnomad4 AFR

AF:

0.193

Gnomad4 AMR

AF:

0.358

Gnomad4 ASJ

AF:

0.454

Gnomad4 EAS

AF:

0.462

Gnomad4 SAS

AF:

0.502

Gnomad4 FIN

AF:

0.566

Gnomad4 NFE

AF:

0.489

Gnomad4 OTH

AF:

0.394

Alfa

AF:

0.470

Hom.:

43103

Bravo

AF:

0.371

TwinsUK

AF:

0.494

AC:

1830

ALSPAC

AF:

0.477

AC:

1837

ESP6500AA

AF:

0.211

AC:

929

ESP6500EA

AF:

0.475

AC:

4081

ExAC

AF:

0.442

AC:

53716

Asia WGS

AF:

0.443

AC:

1541

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Oct 23, 2015

Mayo Clinic Laboratories, Mayo Clinic

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 28, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Beta-D-mannosidosis

Benign:3

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

Sep 05, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:2

Mar 21, 2021

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 29, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.085

BayesDel_addAF

Benign

-0.73

BayesDel_noAF

Benign

-0.68

CADD

Benign

2.4

DANN

Benign

0.79

DEOGEN2

Benign

0.22

.;T;T;.;.

Eigen

Benign

-0.96

Eigen_PC

Benign

-0.94

FATHMM_MKL

Benign

0.056

LIST_S2

Benign

0.61

T;.;T;T;T

MetaRNN

Benign

0.00013

T;T;T;T;T

MetaSVM

Benign

-0.90

MutationAssessor

Benign

1.2

.;L;L;.;.

PrimateAI

Benign

0.25

PROVEAN

Benign

-0.22

.;N;.;.;N

REVEL

Benign

0.032

Sift

Benign

0.45

.;T;.;.;T

Sift4G

Benign

0.39

.;T;.;.;T

Polyphen

0.016, 0.037

.;B;B;.;B

Vest4

0.069, 0.068

MPC

0.063

ClinPred

0.00087

GERP RS

1.3

Varity_R

0.012

gMVP

0.22

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