9-137101088-C-T

Variant names:

• chr9-137101088-C-T
• rs387906886
• NM_016219.5:c.1000C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM2 PM5 PP3_Strong PP5_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. 14/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely 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
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.68
• Publications: 15 publications found

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 Gene-Disease associations (from GenCC):

• MAN1B1-congenital disorder of glycosylation

  Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Rafiq syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• autosomal recessive non-syndromic intellectual disability

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 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 submission is: [Conflicting_classifications_of_pathogenicity].
• 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 [Likely_pathogenic]. Clinvar id is 30415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5	c.1000C>T	p.Arg334Cys	missense_variant	Exon 7 of 13	ENST00000371589.9	NP_057303.2
MAN1B1	XM_006716945.5	c.1000C>T	p.Arg334Cys	missense_variant	Exon 7 of 12		XP_006717008.1
MAN1B1	NR_045720.2	n.1015C>T		non_coding_transcript_exon_variant	Exon 7 of 13
MAN1B1	NR_045721.2	n.1146C>T		non_coding_transcript_exon_variant	Exon 8 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9	c.1000C>T	p.Arg334Cys	missense_variant	Exon 7 of 13	1	NM_016219.5	ENSP00000360645.4

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152186 Hom.: 0 Cov.: 33

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

GnomAD2 exomes AF: 0.0000358 AC: 9 AN: 251440 AF XY: 0.0000147

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 FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461828 Hom.: 0 Cov.: 32 AF XY: 0.0000179 AC XY: 13 AN XY: 727216

African (AFR) AF: 0.000119 AC: 4 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53374

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.0000180 AC: 20 AN: 1111998

Other (OTH) AF: 0.0000331 AC: 2 AN: 60394

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152304 Hom.: 0 Cov.: 33 AF XY: 0.0000269 AC XY: 2 AN XY: 74460

African (AFR) AF: 0.0000962 AC: 4 AN: 41566

American (AMR) AF: 0.000196 AC: 3 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10608

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.0000266 Hom.: 0

Bravo AF: 0.0000378

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rafiq syndrome Pathogenic:3

Mar 15, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces arginine, which is basic and polar, with cysteine, which is neutral and slightly polar, at codon 334 of the MAN1B1 protein (p.Arg334Cys). This variant is present in population databases (rs387906886, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of MAN1B1-related conditions and abnormal glycosylation of serum transferrin showing type II pattern (PMID: 24348268, 27148587). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30415). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. For these reasons, this variant has been classified as Pathogenic. -

Mar 01, 2020

Institute of Human Genetics, University of Leipzig Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Review of the variants reported in Reuter et al., 2017, PMID: 28097321: PM2,PM3_Strong,PP1_Strong,PP3, -

Jul 15, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Inborn genetic diseases Pathogenic:1

Mar 29, 2022

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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. -

See cases Pathogenic:1

Oct 18, 2021

Institute of Human Genetics, University Hospital Muenster

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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

not provided Pathogenic:1

Dec 27, 2023

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27148587, 24566669, 34426522, 34791078, 34258140, 34162022, 36142510, 26279649, 21937992, 24348268, 29908352, 21763484) -

MAN1B1-related disorder Pathogenic:1

Apr 05, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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	D
BayesDel_noAF	Pathogenic	0.43
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.85
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D
M_CAP	Pathogenic	0.53	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	4.1	H;.
PhyloP100		7.7
PrimateAI	Pathogenic	0.84	D
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	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.97
gMVP		0.97
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906886; hg19: chr9-139995540; COSMIC: COSV65378843; COSMIC: COSV65378843;