Genetic Variant MANBA:p.Ser505Pro (chr4-102657873-A-G) – ACMG Classification: Likely_pathogenic (7 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2PP3_StrongPP5

The NM_005908.4(MANBA):c.1513T>C(p.Ser505Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,946 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

MANBA
NM_005908.4 missense

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.77

Publications

7 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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.974

PP5

Variant 4-102657873-A-G is Pathogenic according to our data. Variant chr4-102657873-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 1679.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MANBA	NM_005908.4 link	c.1513T>C	p.Ser505Pro	missense_variant	Exon 12 of 17	ENST00000647097.2	NP_005899.3	O00462
MANBA	XM_047415692.1 link	c.1438T>C	p.Ser480Pro	missense_variant	Exon 13 of 18		XP_047271648.1
MANBA	XM_047415693.1 link	c.1438T>C	p.Ser480Pro	missense_variant	Exon 13 of 18		XP_047271649.1
MANBA	XM_047415694.1 link	c.865T>C	p.Ser289Pro	missense_variant	Exon 8 of 13		XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2 link	c.1513T>C	p.Ser505Pro	missense_variant	Exon 12 of 17		NM_005908.4	ENSP00000495247.1		O00462

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1460946

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726866

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33450

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86230

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53406

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111202

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Beta-D-mannosidosis

Pathogenic:1

Aug 01, 2008

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.97

BayesDel_addAF

Pathogenic

0.47

BayesDel_noAF

Pathogenic

0.44

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.99

.;D;D;.;.

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.94

D;.;D;D;D

M_CAP

Uncertain

0.26

MetaRNN

Pathogenic

0.97

D;D;D;D;D

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.6

.;H;H;.;.

PhyloP100

8.8

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-4.9

.;D;.;.;D

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

.;D;.;.;D

Sift4G

Pathogenic

0.0

.;D;.;.;D

Polyphen

1.0

.;D;D;.;D

Vest4

0.97, 0.98

MutPred

0.85

Loss of glycosylation at T508 (P = 0.0221);Loss of glycosylation at T508 (P = 0.0221);Loss of glycosylation at T508 (P = 0.0221);.;.;

MVP

0.98

MPC

0.48

ClinPred

1.0

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.98

Mutation Taster

=5/95

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.020

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over