4-102723925-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_005908.4(MANBA):c.315G>A(p.Thr105Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0303 in 1,610,210 control chromosomes in the GnomAD database, including 3,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.093 ( 1778 hom., cov: 32)

Exomes 𝑓: 0.024 ( 1868 hom. )

Consequence

MANBA
NM_005908.4 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.401

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

beta-mannosidosis
Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet, ClinGen, Genomics England PanelApp, Ambry Genetics

MANBA links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.69).

BP6

Variant 4-102723925-C-T is Benign according to our data. Variant chr4-102723925-C-T is described in ClinVar as Benign. ClinVar VariationId is 347099.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-0.401 with no splicing effect.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.285 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4 link	c.315G>A	p.Thr105Thr	synonymous_variant	Exon 3 of 17	ENST00000647097.2	NP_005899.3	O00462
MANBA	XM_047415692.1 link	c.240G>A	p.Thr80Thr	synonymous_variant	Exon 4 of 18		XP_047271648.1
MANBA	XM_047415693.1 link	c.240G>A	p.Thr80Thr	synonymous_variant	Exon 4 of 18		XP_047271649.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 link	c.315G>A	p.Thr105Thr	synonymous_variant	Exon 3 of 17		NM_005908.4	ENSP00000495247.1		O00462

Frequencies

GnomAD3 genomes

AF:

0.0932

AC:

14140

AN:

151764

Hom.:

1763

Cov.:

show subpopulations

Gnomad AFR

AF:

0.289

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.0436

Gnomad ASJ

AF:

0.00808

Gnomad EAS

AF:

0.000771

Gnomad SAS

AF:

0.0156

Gnomad FIN

AF:

0.00703

Gnomad MID

AF:

0.0411

Gnomad NFE

AF:

0.0175

Gnomad OTH

AF:

0.0727

GnomAD2 exomes

AF:

0.0348

AC:

8712

AN:

250228

AF XY:

0.0296

show subpopulations

Gnomad AFR exome

AF:

0.300

Gnomad AMR exome

AF:

0.0316

Gnomad ASJ exome

AF:

0.00497

Gnomad EAS exome

AF:

0.000545

Gnomad FIN exome

AF:

0.00791

Gnomad NFE exome

AF:

0.0173

Gnomad OTH exome

AF:

0.0264

GnomAD4 exome

AF:

0.0238

AC:

34643

AN:

1458328

Hom.:

1868

Cov.:

AF XY:

0.0226

AC XY:

16407

AN XY:

725682

show subpopulations

African (AFR)

AF:

0.296

AC:

9831

AN:

33186

American (AMR)

AF:

0.0330

AC:

1472

AN:

44650

Ashkenazi Jewish (ASJ)

AF:

0.00609

AC:

159

AN:

26110

East Asian (EAS)

AF:

0.000328

AC:

AN:

39574

South Asian (SAS)

AF:

0.0164

AC:

1408

AN:

85894

European-Finnish (FIN)

AF:

0.00738

AC:

394

AN:

53390

Middle Eastern (MID)

AF:

0.0452

AC:

260

AN:

5758

European-Non Finnish (NFE)

AF:

0.0171

AC:

18991

AN:

1109482

Other (OTH)

AF:

0.0351

AC:

2115

AN:

60284

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.448

Heterozygous variant carriers

1371

2743

4114

5486

6857

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

856

1712

2568

3424

4280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0935

AC:

14197

AN:

151882

Hom.:

1778

Cov.:

AF XY:

0.0909

AC XY:

6745

AN XY:

74228

show subpopulations

African (AFR)

AF:

0.290

AC:

11988

AN:

41390

American (AMR)

AF:

0.0435

AC:

664

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.00808

AC:

AN:

3464

East Asian (EAS)

AF:

0.000772

AC:

AN:

5178

South Asian (SAS)

AF:

0.0158

AC:

AN:

4806

European-Finnish (FIN)

AF:

0.00703

AC:

AN:

10526

Middle Eastern (MID)

AF:

0.0408

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0175

AC:

1186

AN:

67942

Other (OTH)

AF:

0.0715

AC:

151

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

545

1091

1636

2182

2727

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

130

260

390

520

650

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0372

Hom.:

1082

Bravo

AF:

0.105

Asia WGS

AF:

0.0330

AC:

116

AN:

3474

EpiCase

AF:

0.0182

EpiControl

AF:

0.0183

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:4

May 23, 2018

Athena Diagnostics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jun 13, 2018

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 25, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance:Benign

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Beta-D-mannosidosis

Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.69

CADD

Benign

8.9

(source)

DANN

Benign

0.72

PhyloP100

-0.40

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over