4-102690688-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.114

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]

ACMG classification

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/exons	MANE	UniProt
MANBA	NM_005908.4	c.757G>A	p.Val253Ile	missense_variant	6/17	ENST00000647097.2
MANBA	XM_047415692.1	c.682G>A	p.Val228Ile	missense_variant	7/18
MANBA	XM_047415693.1	c.682G>A	p.Val228Ile	missense_variant	7/18
MANBA	XM_047415694.1	c.109G>A	p.Val37Ile	missense_variant	2/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.757G>A	p.Val253Ile	missense_variant	6/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes AF: 0.397 AC: 60244 AN: 151564 Hom.: 13440 Cov.: 30

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

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

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

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:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Beta-D-mannosidosis Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
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	- -

not specified Benign:2

Likely 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 -

not provided Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Oct 23, 2015	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 28, 2018	- -

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
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
MutationTaster	Benign	1.0	P;P
PrimateAI	Benign	0.25	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

Other links and lift over

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