chr9-137087040-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016219.5(MAN1B1):​c.41C>T​(p.Ser14Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000436 in 1,603,876 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S14S) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

2
1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.800
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 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.07276076).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAN1B1NM_016219.5 linkuse as main transcriptc.41C>T p.Ser14Phe missense_variant 1/13 ENST00000371589.9
MAN1B1XM_006716945.5 linkuse as main transcriptc.41C>T p.Ser14Phe missense_variant 1/12
MAN1B1NR_045720.2 linkuse as main transcriptn.56C>T non_coding_transcript_exon_variant 1/13
MAN1B1NR_045721.2 linkuse as main transcriptn.56C>T non_coding_transcript_exon_variant 1/14

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
MAN1B1ENST00000371589.9 linkuse as main transcriptc.41C>T p.Ser14Phe missense_variant 1/131 NM_016219.5 P2

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152262
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000443
AC:
1
AN:
225598
Hom.:
0
AF XY:
0.00000814
AC XY:
1
AN XY:
122776
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
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:
0.0000100
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000413
AC:
6
AN:
1451614
Hom.:
0
Cov.:
31
AF XY:
0.00000555
AC XY:
4
AN XY:
721166
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:
0.00000451
Gnomad4 OTH exome
AF:
0.0000167
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152262
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74386
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000378
Hom.:
0
Bravo
AF:
0.0000113
ExAC
AF:
0.00000832
AC:
1

ClinVar

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

Submissions by phenotype

Rafiq syndrome Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 12, 2018This 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.11
BayesDel_addAF
Benign
-0.27
T
BayesDel_noAF
Benign
-0.62
CADD
Benign
5.8
DANN
Benign
0.97
DEOGEN2
Benign
0.0075
T
Eigen
Benign
-1.1
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.031
N
LIST_S2
Benign
0.53
T
M_CAP
Benign
0.060
D
MetaRNN
Benign
0.073
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.0
N
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.58
T
PROVEAN
Benign
-0.21
N
REVEL
Benign
0.032
Sift
Pathogenic
0.0
D
Sift4G
Pathogenic
0.0
D
Polyphen
0.087
B
Vest4
0.27
MVP
0.15
MPC
0.18
ClinPred
0.11
T
GERP RS
-2.5
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
2.1
Varity_R
0.071
gMVP
0.16

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs776658507; hg19: chr9-139981492; API