dbSNP rs1555710357: MAN2B1:p.Met1? (chr19-12666700-A-G) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_SupportingPM2

The NM_000528.4(MAN2B1):c.2T>C(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000716 in 1,396,502 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 Uncertain significance (★★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.2e-7 ( 0 hom. )

Consequence

MAN2B1
NM_000528.4 start_lost

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.12

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 links:

ENSG00000269590 (HGNC:):

ENSG00000269590 links:

WDR83 (HGNC:32672): (WD repeat domain 83) This gene encodes a member of the WD-40 protein family. The protein is proposed to function as a molecular scaffold for various multimeric protein complexes. The protein associates with several components of the extracellular signal-regulated kinase (ERK) pathway, and promotes ERK activity in response to serum or other signals. The protein also interacts with egl nine homolog 3 (EGLN3, also known as PHD3) and regulates expression of hypoxia-inducible factor 1, and has been purified as part of the spliceosome. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2009]

WDR83 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PVS1

Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 24 codons. Genomic position: 12666632. Lost 0.023 part of the original CDS.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN2B1	NM_000528.4 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 24	ENST00000456935.7	NP_000519.2	O00754-1
WDR83	NM_001099737.3 link	c.-449A>G		upstream_gene_variant		ENST00000418543.8	NP_001093207.1	Q9BRX9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
MAN2B1	ENST00000456935.7 link	c.2T>C	p.Met1?	start_lost	Exon 1 of 24	1	NM_000528.4	ENSP00000395473.2	O00754-1
ENSG00000269590	ENST00000597961.1 link	c.151-895T>C		intron_variant	Intron 2 of 4	4		ENSP00000472710.1	M0R2P5
WDR83	ENST00000418543.8 link	c.-449A>G		upstream_gene_variant		1	NM_001099737.3	ENSP00000402653.3	Q9BRX9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.16e-7

AC:

AN:

1396502

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

688790

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Deficiency of alpha-mannosidase

Uncertain:2

Apr 27, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Apr 03, 2018

Counsyl

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.20

CADD

Benign

DANN

Benign

0.97

DEOGEN2

Benign

0.14

T;.;.;.

Eigen

Benign

0.12

Eigen_PC

Benign

0.11

FATHMM_MKL

Uncertain

0.90

LIST_S2

Uncertain

0.90

D;D;D;D

M_CAP

Pathogenic

0.67

MetaRNN

Pathogenic

0.99

D;D;D;D

MetaSVM

Uncertain

-0.14

PROVEAN

Benign

-1.5

N;N;.;.

REVEL

Uncertain

0.54

Sift

Pathogenic

0.0

D;D;.;.

Sift4G

Pathogenic

0.0

D;D;.;D

Polyphen

0.68

P;.;.;.

Vest4

0.92

MutPred

1.0

Loss of MoRF binding (P = 0.0686);Loss of MoRF binding (P = 0.0686);Loss of MoRF binding (P = 0.0686);Loss of MoRF binding (P = 0.0686);

MVP

0.91

ClinPred

0.75

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.6

Varity_R

0.96

gMVP

0.88

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over