19-12657507-G-T

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP3_Moderate

The NM_000528.4(MAN2B1):c.1358C>A(p.Ser453Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S453F) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

MAN2B1
NM_000528.4 missense

Scores

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 4.00

Publications

5 publications found

Variant links:

Genes affected

MAN2B1 (HGNC:6826): (mannosidase alpha class 2B member 1) This gene encodes an enzyme that hydrolyzes terminal, non-reducing alpha-D-mannose residues in alpha-D-mannosides. Its activity is necessary for the catabolism of N-linked carbohydrates released during glycoprotein turnover and it is member of family 38 of glycosyl hydrolases. The full length protein is processed in two steps. First, a 49 aa leader sequence is cleaved off and the remainder of the protein is processed into 3 peptides of 70 kDa, 42 kDa (D) and 13/15 kDa (E). Next, the 70 kDa peptide is further processed into three peptides (A, B and C). The A, B and C peptides are disulfide-linked. Defects in this gene have been associated with lysosomal alpha-mannosidosis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Mar 2010]

MAN2B1 Gene-Disease associations (from GenCC):

alpha-mannosidosis
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Myriad Women’s Health, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)

MAN2B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 11 uncertain in NM_000528.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr19-12657507-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 208268.Status of the report is criteria_provided_single_submitter, 1 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.931

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.1358C>A	p.Ser453Tyr	missense_variant	Exon 11 of 24	ENST00000456935.7	NP_000519.2	O00754-1
MAN2B1	NM_001440570.1 link	c.1361C>A	p.Ser454Tyr	missense_variant	Exon 11 of 24		NP_001427499.1
MAN2B1	NM_001173498.2 link	c.1355C>A	p.Ser452Tyr	missense_variant	Exon 11 of 24		NP_001166969.1	O00754-2A8K6A7
MAN2B1	XM_047438841.1 link	c.257C>A	p.Ser86Tyr	missense_variant	Exon 4 of 17		XP_047294797.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN2B1	ENST00000456935.7 link	c.1358C>A	p.Ser453Tyr	missense_variant	Exon 11 of 24	1	NM_000528.4	ENSP00000395473.2		O00754-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1417662

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

701580

African (AFR)

AF:

0.00

AC:

AN:

32626

American (AMR)

AF:

0.00

AC:

AN:

38402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25344

East Asian (EAS)

AF:

0.00

AC:

AN:

37414

South Asian (SAS)

AF:

0.00

AC:

AN:

80916

European-Finnish (FIN)

AF:

0.00

AC:

AN:

48984

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5328

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1090034

Other (OTH)

AF:

0.00

AC:

AN:

58614

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Uncertain:1

Jun 07, 2012

ClinVar Staff, National Center for Biotechnology Information (NCBI)

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.83

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.93

D;.

Eigen

Uncertain

0.47

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Benign

0.68

LIST_S2

Pathogenic

0.97

D;D

M_CAP

Pathogenic

0.37

MetaRNN

Pathogenic

0.93

D;D

MetaSVM

Uncertain

-0.045

MutationAssessor

Pathogenic

3.1

M;.

PhyloP100

4.0

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.7

D;D

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0070

D;D

Sift4G

Uncertain

0.0070

D;D

Polyphen

0.99

D;.

Vest4

0.46

MutPred

0.91

Loss of disorder (P = 0.0286);.;

MVP

0.89

MPC

1.6

ClinPred

0.98

GERP RS

4.9

Varity_R

0.53

gMVP

0.75

Mutation Taster

=9/91

disease causing

(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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over