rs186504463

Positions:

chr9-137097842-T-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_016219.5(MAN1B1):c.635T>G(p.Val212Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00233 in 1,554,764 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0014 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0024 ( 9 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4B:4

Conservation

PhyloP100: 3.39

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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.008163691).

BP6

Variant 9-137097842-T-G is Benign according to our data. Variant chr9-137097842-T-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211430.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=4, Benign=1}.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00141 (214/152162) while in subpopulation NFE AF= 0.00237 (161/67984). AF 95% confidence interval is 0.00207. There are 0 homozygotes in gnomad4. There are 100 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAN1B1	NM_016219.5 linkuse as main transcript	c.635T>G	p.Val212Gly	missense_variant	5/13	ENST00000371589.9
MAN1B1	XM_006716945.5 linkuse as main transcript	c.635T>G	p.Val212Gly	missense_variant	5/12
MAN1B1	NR_045720.2 linkuse as main transcript	n.650T>G		non_coding_transcript_exon_variant	5/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.781T>G		non_coding_transcript_exon_variant	6/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.635T>G	p.Val212Gly	missense_variant	5/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes

AF:

0.00141

AC:

215

AN:

152044

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000338

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000917

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.000754

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00238

Gnomad OTH

AF:

0.00192

GnomAD3 exomes

AF:

0.00172

AC:

277

AN:

160694

Hom.:

AF XY:

0.00172

AC XY:

147

AN XY:

85240

show subpopulations

Gnomad AFR exome

AF:

0.000552

Gnomad AMR exome

AF:

0.000554

Gnomad ASJ exome

AF:

0.000818

Gnomad EAS exome

AF:

0.0000855

Gnomad SAS exome

AF:

0.00261

Gnomad FIN exome

AF:

0.00224

Gnomad NFE exome

AF:

0.00240

Gnomad OTH exome

AF:

0.000892

GnomAD4 exome

AF:

0.00243

AC:

3414

AN:

1402602

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

1674

AN XY:

692298

show subpopulations

Gnomad4 AFR exome

AF:

0.000535

Gnomad4 AMR exome

AF:

0.000718

Gnomad4 ASJ exome

AF:

0.000318

Gnomad4 EAS exome

AF:

0.0000278

Gnomad4 SAS exome

AF:

0.00266

Gnomad4 FIN exome

AF:

0.00216

Gnomad4 NFE exome

AF:

0.00269

Gnomad4 OTH exome

AF:

0.00220

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152162

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74398

show subpopulations

Gnomad4 AFR

AF:

0.000337

Gnomad4 AMR

AF:

0.000916

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00229

Gnomad4 FIN

AF:

0.000754

Gnomad4 NFE

AF:

0.00237

Gnomad4 OTH

AF:

0.00190

Alfa

AF:

0.00200

Hom.:

Bravo

AF:

0.00144

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000232

AC:

ESP6500EA

AF:

0.00142

AC:

ExAC

AF:

0.000814

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rafiq syndrome

Uncertain:2Benign:1

Uncertain significance, 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, 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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 30, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 27, 2023	- -

not provided

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Aug 11, 2023	Has not been previously published as pathogenic or benign to our knowledge; In silico analysis supports that this missense variant has a deleterious effect on protein structure/function -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	MAN1B1: BP4, BS2 -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 25, 2018

The p.V212G variant (also known as c.635T>G), located in coding exon 5 of the MAN1B1 gene, results from a T to G substitution at nucleotide position 635. The valine at codon 212 is replaced by glycine, an amino acid with dissimilar properties. This amino acid position is not well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 24, 2015

- -

MAN1B1-related disorder

Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 04, 2021

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

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.10

CADD

Benign

DANN

Benign

0.95

DEOGEN2

Benign

0.030

T;T

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.62

T;T

MetaRNN

Benign

0.0082

T;T

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.2

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.4

D;.

REVEL

Uncertain

0.34

Sift

Benign

0.041

D;.

Sift4G

Benign

0.098

T;T

Polyphen

0.0090

B;.

Vest4

0.25

MVP

0.65

MPC

0.11

ClinPred

0.026

GERP RS

3.7

Varity_R

0.24

gMVP

0.58

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