rs61744585

Positions:

chr9-137096361-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_016219.5(MAN1B1):c.590C>T(p.Pro197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,613,756 control chromosomes in the GnomAD database, including 1,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.019 ( 96 hom., cov: 32)

Exomes 𝑓: 0.019 ( 1049 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.360

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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0012768805).

BP6

Variant 9-137096361-C-T is Benign according to our data. Variant chr9-137096361-C-T is described in ClinVar as [Benign]. Clinvar id is 129580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137096361-C-T is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAN1B1	NM_016219.5 linkuse as main transcript	c.590C>T	p.Pro197Leu	missense_variant	4/13	ENST00000371589.9	NP_057303.2
MAN1B1	XM_006716945.5 linkuse as main transcript	c.590C>T	p.Pro197Leu	missense_variant	4/12		XP_006717008.1
MAN1B1	NR_045720.2 linkuse as main transcript	n.605C>T		non_coding_transcript_exon_variant	4/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.736C>T		non_coding_transcript_exon_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.590C>T	p.Pro197Leu	missense_variant	4/13	1	NM_016219.5	ENSP00000360645	P2

Frequencies

GnomAD3 genomes

AF:

0.0192

AC:

2927

AN:

152216

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0958

Gnomad ASJ

AF:

0.0199

Gnomad EAS

AF:

0.000577

Gnomad SAS

AF:

0.0186

Gnomad FIN

AF:

0.00518

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.0201

GnomAD3 exomes

AF:

0.0374

AC:

9355

AN:

250174

Hom.:

785

AF XY:

0.0312

AC XY:

4231

AN XY:

135506

show subpopulations

Gnomad AFR exome

AF:

0.00520

Gnomad AMR exome

AF:

0.194

Gnomad ASJ exome

AF:

0.0186

Gnomad EAS exome

AF:

0.000272

Gnomad SAS exome

AF:

0.0179

Gnomad FIN exome

AF:

0.00643

Gnomad NFE exome

AF:

0.0136

Gnomad OTH exome

AF:

0.0259

GnomAD4 exome

AF:

0.0195

AC:

28482

AN:

1461422

Hom.:

1049

Cov.:

AF XY:

0.0187

AC XY:

13628

AN XY:

726976

show subpopulations

Gnomad4 AFR exome

AF:

0.00400

Gnomad4 AMR exome

AF:

0.180

Gnomad4 ASJ exome

AF:

0.0205

Gnomad4 EAS exome

AF:

0.000277

Gnomad4 SAS exome

AF:

0.0183

Gnomad4 FIN exome

AF:

0.00702

Gnomad4 NFE exome

AF:

0.0151

Gnomad4 OTH exome

AF:

0.0162

GnomAD4 genome

AF:

0.0193

AC:

2933

AN:

152334

Hom.:

Cov.:

AF XY:

0.0203

AC XY:

1513

AN XY:

74478

show subpopulations

Gnomad4 AFR

AF:

0.00483

Gnomad4 AMR

AF:

0.0961

Gnomad4 ASJ

AF:

0.0199

Gnomad4 EAS

AF:

0.000579

Gnomad4 SAS

AF:

0.0186

Gnomad4 FIN

AF:

0.00518

Gnomad4 NFE

AF:

0.0147

Gnomad4 OTH

AF:

0.0198

Alfa

AF:

0.0147

Hom.:

Bravo

AF:

0.0278

TwinsUK

AF:

0.0121

AC:

ALSPAC

AF:

0.0127

AC:

ESP6500AA

AF:

0.00590

AC:

ESP6500EA

AF:

0.0135

AC:

116

ExAC

AF:

0.0311

AC:

3775

Asia WGS

AF:

0.0120

AC:

AN:

3478

EpiCase

AF:

0.0125

EpiControl

AF:

0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 05, 2015	- -

Rafiq syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 12, 2019	- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

This alteration is classified as 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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.072

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.46

CADD

Benign

0.42

DANN

Benign

0.89

DEOGEN2

Benign

0.023

T;T

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.051

LIST_S2

Benign

0.59

T;T

MetaRNN

Benign

0.0013

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.1

L;.

MutationTaster

Benign

1.0

N;N

PrimateAI

Benign

0.24

PROVEAN

Benign

-1.1

N;.

REVEL

Benign

0.060

Sift

Benign

0.098

T;.

Sift4G

Benign

0.31

T;T

Polyphen

0.59

P;.

Vest4

0.069

MPC

0.087

ClinPred

0.0032

GERP RS

-3.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.026

gMVP

0.15

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