NM_005908.4:c.757G>A

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

18

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]

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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
MANBANM_005908.4 linkc.757G>A p.Val253Ile missense_variant Exon 6 of 17 ENST00000647097.2 NP_005899.3 O00462
MANBAXM_047415692.1 linkc.682G>A p.Val228Ile missense_variant Exon 7 of 18 XP_047271648.1
MANBAXM_047415693.1 linkc.682G>A p.Val228Ile missense_variant Exon 7 of 18 XP_047271649.1
MANBAXM_047415694.1 linkc.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
MANBAENST00000647097.2 linkc.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.:
30
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.:
33
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.:
30
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
Jun 28, 2018
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

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

- -

Beta-D-mannosidosis Benign:3
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

- -

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. -

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
T
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
N
LIST_S2
Benign
0.61
T;.;T;T;T
MetaRNN
Benign
0.00013
T;T;T;T;T
MetaSVM
Benign
-0.90
T
MutationAssessor
Benign
1.2
.;L;L;.;.
PrimateAI
Benign
0.25
T
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
T
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.

Other links and lift over

dbSNP: rs227368; hg19: chr4-103611845; COSMIC: COSV56963409; API