rs12000048

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The ENST00000371589.9(MAN1B1):ā€‹c.1713C>Gā€‹(p.Ile571Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000205 in 1,613,322 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 (ā˜…). Synonymous variant affecting the same amino acid position (i.e. I571I) has been classified as Likely benign.

Frequency

Genomes: š‘“ 0.0000066 ( 0 hom., cov: 34)
Exomes š‘“: 0.000022 ( 0 hom. )

Consequence

MAN1B1
ENST00000371589.9 missense

Scores

3
11
5

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.787
Variant links:
Genes affected
MAN1B1 (HGNC:6823): (mannosidase alpha class 1B member 1) This gene encodes an enzyme belonging to the glycosyl hydrolase 47 family. This enzyme functions in N-glycan biosynthesis, and is a class I alpha-1,2-mannosidase that specifically converts Man9GlcNAc to Man8GlcNAc isomer B. It is required for N-glycan trimming to Man5-6GlcNAc2 in the endoplasmic-reticulum-associated degradation pathway. Mutations in this gene cause autosomal-recessive intellectual disability. Alternative splicing results in multiple transcript variants. A related pseudogene has been identified on chromosome 11. [provided by RefSeq, Dec 2011]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.85

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
MAN1B1NM_016219.5 linkuse as main transcriptc.1713C>G p.Ile571Met missense_variant 11/13 ENST00000371589.9 NP_057303.2
MAN1B1XM_006716945.5 linkuse as main transcriptc.1713C>G p.Ile571Met missense_variant 11/12 XP_006717008.1
MAN1B1NR_045720.2 linkuse as main transcriptn.1703C>G non_coding_transcript_exon_variant 11/13
MAN1B1NR_045721.2 linkuse as main transcriptn.1859C>G non_coding_transcript_exon_variant 12/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
MAN1B1ENST00000371589.9 linkuse as main transcriptc.1713C>G p.Ile571Met missense_variant 11/131 NM_016219.5 ENSP00000360645 P2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000159
AC:
4
AN:
251296
Hom.:
0
AF XY:
0.0000221
AC XY:
3
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000264
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000219
AC:
32
AN:
1461118
Hom.:
0
Cov.:
31
AF XY:
0.0000151
AC XY:
11
AN XY:
726884
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000224
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:
0.0000270
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
34
AF XY:
0.0000134
AC XY:
1
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
TwinsUK
AF:
0.000270
AC:
1
ALSPAC
AF:
0.00
AC:
0
EpiCase
AF:
0.0000545
EpiControl
AF:
0.00

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingGeneDxAug 23, 2019Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.58
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
0.060
CADD
Benign
19
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.53
D;D
Eigen
Benign
-0.18
Eigen_PC
Benign
-0.30
FATHMM_MKL
Benign
0.36
N
LIST_S2
Uncertain
0.92
D;D
M_CAP
Pathogenic
0.30
D
MetaRNN
Pathogenic
0.85
D;D
MetaSVM
Benign
-0.48
T
MutationAssessor
Uncertain
2.6
M;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Uncertain
0.53
T
PROVEAN
Uncertain
-2.6
D;.
REVEL
Uncertain
0.64
Sift
Uncertain
0.0010
D;.
Sift4G
Uncertain
0.0040
D;D
Polyphen
0.99
D;.
Vest4
0.79
MutPred
0.62
Gain of disorder (P = 0.0085);.;
MVP
0.87
MPC
0.43
ClinPred
0.89
D
GERP RS
-0.13
Varity_R
0.80
gMVP
0.59

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.030
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.

Other links and lift over

dbSNP: rs12000048; hg19: chr9-140001848; API