rs75442795

Positions:

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 2P and 16B. PM2BP4_StrongBP6_Very_StrongBS1

The NM_016219.5(MAN1B1):c.403G>A(p.Val135Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000444 in 1,613,966 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0016 ( 1 hom., cov: 33)

Exomes 𝑓: 0.00032 ( 0 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts P:1B:5

Conservation

PhyloP100: 3.40

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:

MAN1B1 (HGNC:):

MAN1B1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0060478747).

BP6

Variant 9-137088943-G-A is Benign according to our data. Variant chr9-137088943-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 129579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00164 (250/152302) while in subpopulation AFR AF= 0.00534 (222/41554). AF 95% confidence interval is 0.00477. There are 1 homozygotes in gnomad4. There are 128 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1B1	NM_016219.5 linkuse as main transcript	c.403G>A	p.Val135Ile	missense_variant	3/13	ENST00000371589.9	NP_057303.2	Q9UKM7
MAN1B1	XM_006716945.5 linkuse as main transcript	c.403G>A	p.Val135Ile	missense_variant	3/12		XP_006717008.1	H0YG20
MAN1B1	NR_045720.2 linkuse as main transcript	n.418G>A		non_coding_transcript_exon_variant	3/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.549G>A		non_coding_transcript_exon_variant	4/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.403G>A	p.Val135Ile	missense_variant	3/13	1	NM_016219.5	ENSP00000360645.4		Q9UKM7

Frequencies

GnomAD3 genomes

AF:

0.00162

AC:

247

AN:

152184

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00529

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000851

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000176

Gnomad OTH

AF:

0.000955

GnomAD3 exomes

AF:

0.000466

AC:

117

AN:

251326

Hom.:

AF XY:

0.000368

AC XY:

AN XY:

135888

show subpopulations

Gnomad AFR exome

AF:

0.00493

Gnomad AMR exome

AF:

0.000405

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000653

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000176

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000319

AC:

467

AN:

1461664

Hom.:

Cov.:

AF XY:

0.000290

AC XY:

211

AN XY:

727110

show subpopulations

Gnomad4 AFR exome

AF:

0.00523

Gnomad4 AMR exome

AF:

0.000492

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000812

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000209

Gnomad4 OTH exome

AF:

0.000513

GnomAD4 genome

AF:

0.00164

AC:

250

AN:

152302

Hom.:

Cov.:

AF XY:

0.00172

AC XY:

128

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.00534

Gnomad4 AMR

AF:

0.000850

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000176

Gnomad4 OTH

AF:

0.000945

Alfa

AF:

0.000359

Hom.:

Bravo

AF:

0.00147

ESP6500AA

AF:

0.00409

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.000527

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000237

ClinVar

Significance: Benign/Likely benign

Submissions summary: Pathogenic:1Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Pathogenic:1Benign:2

Likely pathogenic, flagged submission	clinical testing	Biochemical Molecular Genetic Laboratory, King Abdulaziz Medical City	Sep 26, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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 and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 03, 2019

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 28, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

MAN1B1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 21, 2020

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.081

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.34

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0094

T;T

Eigen

Benign

0.029

Eigen_PC

Benign

0.13

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.73

T;T

M_CAP

Uncertain

0.096

MetaRNN

Benign

0.0060

T;T

MetaSVM

Benign

-0.84

MutationAssessor

Benign

1.9

L;.

PrimateAI

Benign

0.37

PROVEAN

Benign

-0.28

N;.

REVEL

Benign

0.18

Sift

Benign

0.14

T;.

Sift4G

Benign

0.41

T;T

Polyphen

0.29

B;.

Vest4

0.25

MVP

0.75

MPC

0.064

ClinPred

0.019

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.064

gMVP

0.18

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