rs138658585

Positions:

chr9-137106303-A-G

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_016219.5(MAN1B1):c.1433A>G(p.Lys478Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0024 in 1,552,362 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0025 ( 1 hom., cov: 34)

Exomes 𝑓: 0.0024 ( 6 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:6

Conservation

PhyloP100: 4.16

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 Benign. Variant got -9 ACMG points.

BP6

Variant 9-137106303-A-G is Benign according to our data. Variant chr9-137106303-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211420.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=2, Uncertain_significance=1}. Variant chr9-137106303-A-G is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00248 (378/152310) while in subpopulation NFE AF= 0.00316 (215/68012). AF 95% confidence interval is 0.00281. There are 1 homozygotes in gnomad4. There are 206 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAN1B1	NM_016219.5 linkuse as main transcript	c.1433A>G	p.Lys478Arg	missense_variant	9/13	ENST00000371589.9	NP_057303.2
MAN1B1	XM_006716945.5 linkuse as main transcript	c.1433A>G	p.Lys478Arg	missense_variant	9/12		XP_006717008.1
MAN1B1	NR_045720.2 linkuse as main transcript	n.1448A>G		non_coding_transcript_exon_variant	9/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.1579A>G		non_coding_transcript_exon_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.1433A>G	p.Lys478Arg	missense_variant	9/13	1	NM_016219.5	ENSP00000360645	P2

Frequencies

GnomAD3 genomes

AF:

0.00248

AC:

378

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000410

Gnomad AMI

AF:

0.0154

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00186

Gnomad FIN

AF:

0.0109

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00316

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00238

AC:

376

AN:

157780

Hom.:

AF XY:

0.00229

AC XY:

192

AN XY:

83674

show subpopulations

Gnomad AFR exome

AF:

0.000334

Gnomad AMR exome

AF:

0.000242

Gnomad ASJ exome

AF:

0.000591

Gnomad EAS exome

AF:

0.0000860

Gnomad SAS exome

AF:

0.00122

Gnomad FIN exome

AF:

0.0105

Gnomad NFE exome

AF:

0.00262

Gnomad OTH exome

AF:

0.00203

GnomAD4 exome

AF:

0.00239

AC:

3345

AN:

1400052

Hom.:

Cov.:

AF XY:

0.00241

AC XY:

1662

AN XY:

690768

show subpopulations

Gnomad4 AFR exome

AF:

0.000219

Gnomad4 AMR exome

AF:

0.000530

Gnomad4 ASJ exome

AF:

0.000754

Gnomad4 EAS exome

AF:

0.0000275

Gnomad4 SAS exome

AF:

0.00122

Gnomad4 FIN exome

AF:

0.0103

Gnomad4 NFE exome

AF:

0.00241

Gnomad4 OTH exome

AF:

0.00164

GnomAD4 genome

AF:

0.00248

AC:

378

AN:

152310

Hom.:

Cov.:

AF XY:

0.00277

AC XY:

206

AN XY:

74470

show subpopulations

Gnomad4 AFR

AF:

0.000409

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00187

Gnomad4 FIN

AF:

0.0109

Gnomad4 NFE

AF:

0.00316

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.00251

Hom.:

Bravo

AF:

0.00167

TwinsUK

AF:

0.00162

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.000233

AC:

ESP6500EA

AF:

0.00155

AC:

ExAC

AF:

0.00135

AC:

144

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rafiq syndrome

Uncertain:1Benign:1

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 27, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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, 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. -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Dec 01, 2016	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	MAN1B1: BP4, BS1, BS2 -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jun 30, 2015

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 27, 2018

This alteration is classified as likely 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

Nov 29, 2023

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

0.079

BayesDel_addAF

Benign

-0.26

BayesDel_noAF

Benign

-0.15

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-0.067

Eigen_PC

Benign

0.041

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.89

D;D

MetaRNN

Benign

0.0077

T;T

MetaSVM

Benign

-0.52

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.9

N;.

REVEL

Uncertain

0.38

Sift

Benign

0.26

T;.

Sift4G

Benign

0.23

T;T

Polyphen

0.073

B;.

Vest4

0.31

MVP

0.81

MPC

0.12

ClinPred

0.011

GERP RS

3.9

Varity_R

0.29

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.21

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.21

Position offset: -33

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