rs387906886

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM2PM5PP3_StrongPP5_Very_Strong

The NM_016219.5(MAN1B1):c.1000C>T(p.Arg334Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000229 in 1,614,132 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R334H) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 7.68

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]

MAN1B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr9-137101089-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1218674.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

PP5

Variant 9-137101088-C-T is Pathogenic according to our data. Variant chr9-137101088-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 30415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137101088-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAN1B1	NM_016219.5 linkuse as main transcript	c.1000C>T	p.Arg334Cys	missense_variant	7/13	ENST00000371589.9
MAN1B1	XM_006716945.5 linkuse as main transcript	c.1000C>T	p.Arg334Cys	missense_variant	7/12
MAN1B1	NR_045720.2 linkuse as main transcript	n.1015C>T		non_coding_transcript_exon_variant	7/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.1146C>T		non_coding_transcript_exon_variant	8/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.1000C>T	p.Arg334Cys	missense_variant	7/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes

AF:

0.0000591

AC:

AN:

152186

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000965

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000196

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:

0.000478

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251440

Hom.:

AF XY:

0.0000147

AC XY:

AN XY:

135916

show subpopulations

Gnomad AFR exome

AF:

0.000185

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000264

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000192

AC:

AN:

1461828

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727216

show subpopulations

Gnomad4 AFR exome

AF:

0.000119

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000180

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000591

AC:

AN:

152304

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0000962

Gnomad4 AMR

AF:

0.000196

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:

0.000473

Alfa

AF:

0.0000844

Hom.:

Bravo

AF:

0.0000378

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jul 15, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Mar 01, 2020	Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM3_Strong,PP1_Strong,PP3, -

Global developmental delay

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Oct 18, 2021

ACMG categories: PS5,PM1,PM2,PP3,PP5 -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 29, 2022

The c.1000C>T (p.R334C) alteration is located in exon 7 (coding exon 7) of the MAN1B1 gene. This alteration results from a C to T substitution at nucleotide position 1000, causing the arginine (R) at amino acid position 334 to be replaced by a cysteine (C). Based on data from gnomAD, the T allele has an overall frequency of <0.01% (10/282840) total alleles studied. The highest observed frequency was 0.02% (4/24956) of African alleles. This alteration has been identified in the homozygous or compound heterozygous state in multiple individuals with intellectual disability and/or other clinical presentations consistent with MAN1B1-related congenital disorder of glycosylation (CDG) type II (Rafiq, 2011; Najmabadi, 2011; Rymen, 2013; Van Scherpenzeel, 2014; Hoffjan, 2015). This amino acid position is highly conserved in available vertebrate species. Studies in HEK293 cells showed decreased expression of the variant protein and reduction in kinetic efficiency of the enzyme compared to wild type, while studies in patient derived fibroblasts indicated this alteration would lead to reduced protein expression, N-Glycan abnormalities, and altered Golgi morphology (Rafiq, 2011; Rymen, 2013). This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

MAN1B1-related disorder

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 05, 2019

The MAN1B1 c.1000C>T (p.Arg334Cys) missense variant has been reported in seven individuals from three families with autosomal recessive intellectual disability. Rafiq et al. (2011) identified the variant in a homozygous state in three affected siblings from a non-consanguineous Iranian family, Hoffjan et al. (2015) found the variant in a homozygous state in three affected siblings from a consanguineous Turkish family, and Balasubramanian et al. (2018) detected the variant in a compound heterozygous state with a frameshift variant in one affected individual of European descent. The variant was said to segregate with disease in the Iranian and Turkish families. The p.Arg334Cys variant has been further reported in a homozygous state in six individuals from five families with a diagnosis of congenital disorders of glycosylation (Rymen et al. 2013; Van Scherpenzeel et al. 2014; Gupta et al. 2016). The p.Arg334Cys variant was absent from 346 Iranian and German controls and is reported at a frequency of 0.000167 in the African population of the Genome Aggregation Database. Expression of wild type and p.Arg334Cys variant constructs in HEK293 cells showed that the variant protein was expressed and secreted at 20% of the wild type levels, with a reduction in the kinetic efficiency of the enzyme compared to wild type (Rafiq et al. 2011). Based on the collective evidence, the p.Arg334Cys variant is classified as pathogenic for MAN1B1-related disorders. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.91

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.43

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Pathogenic

0.82

D;D

Eigen

Pathogenic

0.97

Eigen_PC

Pathogenic

0.85

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

D;D

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.98

D;D

MetaSVM

Pathogenic

1.1

MutationAssessor

Pathogenic

4.1

H;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Pathogenic

-7.4

D;.

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

D;.

Sift4G

Pathogenic

0.0

D;D

Polyphen

1.0

D;.

Vest4

1.0

MutPred

0.90

Gain of catalytic residue at F329 (P = 0.1623);.;

MVP

0.98

MPC

0.51

ClinPred

1.0

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.97

gMVP

0.97

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.

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