rs140496149

Variant names:

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_ModerateBP6BP7BS1BS2

The NM_016219.5(MAN1B1):c.1980C>T(p.Phe660Phe) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00196 in 1,613,942 control chromosomes in the GnomAD database, including 8 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 0.0017 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0020 ( 8 hom. )

Consequence

MAN1B1
NM_016219.5 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:4

Conservation

PhyloP100: -0.0370

Publications

0 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: Orphanet, ClinGen
Rafiq syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -12 ACMG points.

BP4

Computational evidence support a benign effect (REVEL=0.133).

BP6

Variant 9-137108471-C-T is Benign according to our data. Variant chr9-137108471-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 211426.

BP7

Synonymous conserved (PhyloP=-0.037 with no splicing effect.

BS1

Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00168 (256/152278) while in subpopulation SAS AF = 0.0083 (40/4818). AF 95% confidence interval is 0.00627. There are 0 homozygotes in GnomAd4. There are 127 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 8 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MAN1B1	NM_016219.5 link	c.1980C>T	p.Phe660Phe	synonymous_variant	Exon 13 of 13	ENST00000371589.9	NP_057303.2	Q9UKM7
MAN1B1	NR_045720.2 link	n.1970C>T		non_coding_transcript_exon_variant	Exon 13 of 13
MAN1B1	NR_045721.2 link	n.2126C>T		non_coding_transcript_exon_variant	Exon 14 of 14
MAN1B1	XM_006716945.5 link	c.*509C>T		downstream_gene_variant			XP_006717008.1	H0YG20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 link	c.1980C>T	p.Phe660Phe	synonymous_variant	Exon 13 of 13	1	NM_016219.5	ENSP00000360645.4		Q9UKM7

Frequencies

GnomAD3 genomes

AF:

0.00168

AC:

256

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000290

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00830

Gnomad FIN

AF:

0.00151

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00268

Gnomad OTH

AF:

0.000479

GnomAD2 exomes

AF:

0.00210

AC:

527

AN:

251472

AF XY:

0.00235

show subpopulations

Gnomad AFR exome

AF:

0.000246

Gnomad AMR exome

AF:

0.000607

Gnomad ASJ exome

AF:

0.000794

Gnomad EAS exome

AF:

0.0000544

Gnomad FIN exome

AF:

0.000970

Gnomad NFE exome

AF:

0.00244

Gnomad OTH exome

AF:

0.00228

GnomAD4 exome

AF:

0.00199

AC:

2902

AN:

1461664

Hom.:

Cov.:

AF XY:

0.00221

AC XY:

1607

AN XY:

727136

show subpopulations

African (AFR)

AF:

0.000209

AC:

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000727

AC:

AN:

26136

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39700

South Asian (SAS)

AF:

0.00624

AC:

538

AN:

86258

European-Finnish (FIN)

AF:

0.00111

AC:

AN:

53222

Middle Eastern (MID)

AF:

0.00572

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00189

AC:

2106

AN:

1111986

Other (OTH)

AF:

0.00189

AC:

114

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

205

410

616

821

1026

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

124

186

248

310

<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:

0.00168

AC:

256

AN:

152278

Hom.:

Cov.:

AF XY:

0.00171

AC XY:

127

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000289

AC:

AN:

41546

American (AMR)

AF:

0.000327

AC:

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00830

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00151

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00268

AC:

182

AN:

68022

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00236

Hom.:

Bravo

AF:

0.00113

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00273

EpiControl

AF:

0.00267

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Rafiq syndrome

Benign:2

Jan 08, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Likely benign

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 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. -

not specified

Uncertain:1

Sep 14, 2014

Genetic Services Laboratory, University of Chicago

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Benign:1

May 15, 2016

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

not provided

Benign:1

Mar 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

MAN1B1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.37

CADD

Benign

4.5

(source)

DANN

Benign

0.84

PhyloP100

-0.037

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.1

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over