dbSNP rs186504463: MAN1B1:p.Val212Gly (chr9-137097842-T-G) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. The variant received -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. 13/21 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

Publications

5 publications found

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 Gene-Disease associations (from GenCC):

MAN1B1-congenital disorder of glycosylation
Inheritance: AR Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
Rafiq syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MAN1B1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 211430.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 9 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAN1B1	NM_016219.5	MANE Select	c.635T>G	p.Val212Gly	missense	Exon 5 of 13	NP_057303.2	Q9UKM7
MAN1B1	NR_045720.2		n.650T>G		non_coding_transcript_exon	Exon 5 of 13
MAN1B1	NR_045721.2		n.781T>G		non_coding_transcript_exon	Exon 6 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.635T>G	p.Val212Gly	missense	Exon 5 of 13	ENSP00000360645.4	Q9UKM7
MAN1B1	ENST00000371587.9	TSL:1	n.*337T>G		non_coding_transcript_exon	Exon 6 of 14	ENSP00000483132.2	A0A087X064
MAN1B1	ENST00000544448.6	TSL:1	n.635T>G		non_coding_transcript_exon	Exon 5 of 13	ENSP00000444966.2	H0YGV7

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

GnomAD2 exomes

AF:

0.00172

AC:

277

AN:

160694

AF XY:

0.00172

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 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

African (AFR)

AF:

0.000535

AC:

AN:

31768

American (AMR)

AF:

0.000718

AC:

AN:

36226

Ashkenazi Jewish (ASJ)

AF:

0.000318

AC:

AN:

25196

East Asian (EAS)

AF:

0.0000278

AC:

AN:

35972

South Asian (SAS)

AF:

0.00266

AC:

211

AN:

79418

European-Finnish (FIN)

AF:

0.00216

AC:

105

AN:

48636

Middle Eastern (MID)

AF:

0.00141

AC:

AN:

5692

European-Non Finnish (NFE)

AF:

0.00269

AC:

2910

AN:

1081512

Other (OTH)

AF:

0.00220

AC:

128

AN:

58182

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

159

318

477

636

795

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

114

228

342

456

570

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00141

AC:

214

AN:

152162

Hom.:

Cov.:

AF XY:

0.00134

AC XY:

100

AN XY:

74398

show subpopulations

African (AFR)

AF:

0.000337

AC:

AN:

41510

American (AMR)

AF:

0.000916

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00229

AC:

AN:

4814

European-Finnish (FIN)

AF:

0.000754

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00237

AC:

161

AN:

67984

Other (OTH)

AF:

0.00190

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00201

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

ClinVar submissions

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

Rafiq syndrome (3)

not provided (2)

Inborn genetic diseases (1)

MAN1B1-related disorder (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Benign

-0.22

BayesDel_noAF

Benign

-0.10

CADD

Benign

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.030

Eigen

Benign

-0.37

Eigen_PC

Benign

-0.35

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.62

MetaRNN

Benign

0.0082

MetaSVM

Benign

-0.82

MutationAssessor

Benign

1.2

PhyloP100

3.4

PrimateAI

Benign

0.34

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.34

Sift

Benign

0.041

Sift4G

Benign

0.098

Polyphen

0.0090

Vest4

0.25

MVP

0.65

MPC

0.11

ClinPred

0.026

GERP RS

3.7

Varity_R

0.24

gMVP

0.58

Mutation Taster

=85/15

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over