rs575361734

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

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

The NM_016219.5(MAN1B1):c.213C>G(p.Cys71Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000301 in 1,577,202 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00012 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 1 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:5

Conservation

PhyloP100: 1.28

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:

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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=0.10550359).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5 link	c.213C>G	p.Cys71Trp	missense_variant	Exon 1 of 13	ENST00000371589.9	NP_057303.2	Q9UKM7
MAN1B1	XM_006716945.5 link	c.213C>G	p.Cys71Trp	missense_variant	Exon 1 of 12		XP_006717008.1	H0YG20
MAN1B1	NR_045720.2 link	n.228C>G		non_coding_transcript_exon_variant	Exon 1 of 13
MAN1B1	NR_045721.2 link	n.228C>G		non_coding_transcript_exon_variant	Exon 1 of 14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 link	c.213C>G	p.Cys71Trp	missense_variant	Exon 1 of 13	1	NM_016219.5	ENSP00000360645.4		Q9UKM7

Frequencies

GnomAD3 genomes

AF:

0.000125

AC:

AN:

152230

Hom.:

Cov.:

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:

0.0000941

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000250

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000163

AC:

AN:

177722

Hom.:

AF XY:

0.000113

AC XY:

AN XY:

97222

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000729

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000367

Gnomad NFE exome

AF:

0.000297

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000319

AC:

455

AN:

1424854

Hom.:

Cov.:

AF XY:

0.000305

AC XY:

215

AN XY:

705460

show subpopulations

Gnomad4 AFR exome

AF:

0.0000906

Gnomad4 AMR exome

AF:

0.0000512

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.000246

Gnomad4 NFE exome

AF:

0.000378

Gnomad4 OTH exome

AF:

0.000407

GnomAD4 genome

AF:

0.000125

AC:

AN:

152348

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74504

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:

0.0000941

Gnomad4 NFE

AF:

0.000250

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000337

Hom.:

Bravo

AF:

0.000136

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000259

AC:

ExAC

AF:

0.000148

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Uncertain:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This 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. -

Aug 23, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces cysteine, which is neutral and slightly polar, with tryptophan, which is neutral and slightly polar, at codon 71 of the MAN1B1 protein (p.Cys71Trp). This variant is present in population databases (rs575361734, gnomAD 0.03%). 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: 211427). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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. -

not specified

Uncertain:1

Jun 01, 2015

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases

Uncertain:1

Sep 28, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.213C>G (p.C71W) alteration is located in exon 1 (coding exon 1) of the MAN1B1 gene. This alteration results from a C to G substitution at nucleotide position 213, causing the cysteine (C) at amino acid position 71 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Uncertain:1

Jul 13, 2022

GeneDx

Significance: Uncertain significance

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; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.28

BayesDel_noAF

Benign

-0.34

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.17

T;T

Eigen

Benign

0.076

Eigen_PC

Benign

0.092

FATHMM_MKL

Uncertain

0.84

LIST_S2

Benign

0.81

T;T

M_CAP

Pathogenic

0.39

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.8

L;.

PrimateAI

Uncertain

0.65

PROVEAN

Uncertain

-3.7

D;.

REVEL

Benign

0.22

Sift

Uncertain

0.0080

D;.

Sift4G

Uncertain

0.0060

D;D

Polyphen

1.0

D;.

Vest4

0.52

MVP

0.33

MPC

0.45

ClinPred

0.33

GERP RS

3.3

Varity_R

0.77

gMVP

0.60

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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