rs144672735

Positions:

chr9-137107319-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016219.5(MAN1B1):c.1636A>G(p.Met546Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000545 in 1,613,214 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000049 ( 0 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:4

Conservation

PhyloP100: 3.69

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
MAN1B1	NM_016219.5 linkuse as main transcript	c.1636A>G	p.Met546Val	missense_variant	11/13	ENST00000371589.9
MAN1B1	XM_006716945.5 linkuse as main transcript	c.1636A>G	p.Met546Val	missense_variant	11/12
MAN1B1	NR_045720.2 linkuse as main transcript	n.1626A>G		non_coding_transcript_exon_variant	11/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.1782A>G		non_coding_transcript_exon_variant	12/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.1636A>G	p.Met546Val	missense_variant	11/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes

AF:

0.000112

AC:

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000193

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.0000997

AC:

AN:

250804

Hom.:

AF XY:

0.0000957

AC XY:

AN XY:

135806

show subpopulations

Gnomad AFR exome

AF:

0.000248

Gnomad AMR exome

AF:

0.000318

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000486

AC:

AN:

1460876

Hom.:

Cov.:

AF XY:

0.0000495

AC XY:

AN XY:

726762

show subpopulations

Gnomad4 AFR exome

AF:

0.000209

Gnomad4 AMR exome

AF:

0.000224

Gnomad4 ASJ exome

AF:

0.0000765

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000191

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.000166

GnomAD4 genome

AF:

0.000112

AC:

AN:

152338

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74496

show subpopulations

Gnomad4 AFR

AF:

0.000192

Gnomad4 AMR

AF:

0.0000653

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000442

Hom.:

Bravo

AF:

0.0000907

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000140

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.000356

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	Jan 19, 2022	- -
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 specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 12, 2016

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

The c.1636A>G (p.M546V) alteration is located in exon 11 (coding exon 11) of the MAN1B1 gene. This alteration results from a A to G substitution at nucleotide position 1636, causing the methionine (M) at amino acid position 546 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.064

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.45

T;T

Eigen

Benign

-0.0013

Eigen_PC

Benign

0.054

FATHMM_MKL

Uncertain

0.93

LIST_S2

Uncertain

0.95

D;D

M_CAP

Uncertain

0.27

MetaRNN

Uncertain

0.53

D;D

MetaSVM

Benign

-0.70

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.60

PROVEAN

Uncertain

-3.0

D;.

REVEL

Uncertain

0.41

Sift

Uncertain

0.010

D;.

Sift4G

Benign

0.085

T;T

Polyphen

0.64

P;.

Vest4

0.67

MVP

0.63

MPC

0.15

ClinPred

0.079

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.42

gMVP

0.65

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