chr9-137087025-G-C

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2BP4_StrongBS1_Supporting

The NM_016219.5(MAN1B1):ā€‹c.26G>Cā€‹(p.Ser9Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000592 in 1,601,582 control chromosomes in the GnomAD database, including 1 homozygotes. 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 (ā˜…ā˜…).

Frequency

Genomes: š‘“ 0.00030 ( 0 hom., cov: 34)
Exomes š‘“: 0.00062 ( 1 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 0.509
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.027214408).
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000302 (46/152274) while in subpopulation NFE AF= 0.000661 (45/68046). AF 95% confidence interval is 0.000507. There are 0 homozygotes in gnomad4. There are 19 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
MAN1B1NM_016219.5 linkuse as main transcriptc.26G>C p.Ser9Thr missense_variant 1/13 ENST00000371589.9
MAN1B1XM_006716945.5 linkuse as main transcriptc.26G>C p.Ser9Thr missense_variant 1/12
MAN1B1NR_045720.2 linkuse as main transcriptn.41G>C non_coding_transcript_exon_variant 1/13
MAN1B1NR_045721.2 linkuse as main transcriptn.41G>C 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.26G>C p.Ser9Thr missense_variant 1/131 NM_016219.5 P2

Frequencies

GnomAD3 genomes
AF:
0.000302
AC:
46
AN:
152274
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:
0.000661
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000202
AC:
45
AN:
222516
Hom.:
0
AF XY:
0.000223
AC XY:
27
AN XY:
120958
show subpopulations
Gnomad AFR exome
AF:
0.000146
Gnomad AMR exome
AF:
0.0000312
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:
0.000407
Gnomad OTH exome
AF:
0.000372
GnomAD4 exome
AF:
0.000622
AC:
902
AN:
1449308
Hom.:
1
Cov.:
31
AF XY:
0.000596
AC XY:
429
AN XY:
719822
show subpopulations
Gnomad4 AFR exome
AF:
0.000180
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:
0.000736
Gnomad4 OTH exome
AF:
0.00135
GnomAD4 genome
AF:
0.000302
AC:
46
AN:
152274
Hom.:
0
Cov.:
34
AF XY:
0.000255
AC XY:
19
AN XY:
74408
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:
0.000661
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000380
Hom.:
0
Bravo
AF:
0.000363
TwinsUK
AF:
0.00108
AC:
4
ALSPAC
AF:
0.000519
AC:
2
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000700
AC:
6
ExAC
AF:
0.000117
AC:
14

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

Rafiq syndrome Uncertain:2
Uncertain significance, criteria provided, single submitterclinical testingInvitaeSep 07, 2022This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 9 of the MAN1B1 protein (p.Ser9Thr). This variant is present in population databases (rs140568381, gnomAD 0.04%). This variant has not been reported in the literature in individuals affected with MAN1B1-related conditions. ClinVar contains an entry for this variant (Variation ID: 588165). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 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. -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJan 25, 2018The p.S9T variant (also known as c.26G>C), located in coding exon 1 of the MAN1B1 gene, results from a G to C substitution at nucleotide position 26. The serine at codon 9 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.084
BayesDel_addAF
Benign
-0.49
T
BayesDel_noAF
Benign
-0.60
CADD
Benign
6.2
DANN
Benign
0.75
DEOGEN2
Benign
0.0070
T
Eigen
Benign
-1.2
Eigen_PC
Benign
-1.2
FATHMM_MKL
Benign
0.11
N
LIST_S2
Benign
0.35
T
M_CAP
Benign
0.019
T
MetaRNN
Benign
0.027
T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
0.69
N
MutationTaster
Benign
1.0
N
PrimateAI
Uncertain
0.56
T
PROVEAN
Benign
-0.090
N
REVEL
Benign
0.040
Sift
Benign
0.63
T
Sift4G
Benign
0.80
T
Polyphen
0.0
B
Vest4
0.18
MVP
0.14
MPC
0.070
ClinPred
0.010
T
GERP RS
1.5
Varity_R
0.075
gMVP
0.14

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: rs140568381; hg19: chr9-139981477; COSMIC: COSV100814562; COSMIC: COSV100814562; API