chr9-137101647-G-A

Position:

chr9-137101647-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_016219.5(MAN1B1):c.1229G>A(p.Arg410His) variant causes a missense change. The variant allele was found at a frequency of 0.000681 in 1,612,990 control chromosomes in the GnomAD database, including 19 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0011 ( 2 hom., cov: 34)

Exomes 𝑓: 0.00063 ( 17 hom. )

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 4.62

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:

MAN1B1 (HGNC:):

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=0.015785038).

BP6

Variant 9-137101647-G-A is Benign according to our data. Variant chr9-137101647-G-A is described in ClinVar as [Benign]. Clinvar id is 129569.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00114 (173/152368) while in subpopulation EAS AF= 0.0264 (137/5190). AF 95% confidence interval is 0.0228. There are 2 homozygotes in gnomad4. There are 92 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1B1	NM_016219.5 linkuse as main transcript	c.1229G>A	p.Arg410His	missense_variant	8/13	ENST00000371589.9	NP_057303.2	Q9UKM7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.1229G>A	p.Arg410His	missense_variant	8/13	1	NM_016219.5	ENSP00000360645.4		Q9UKM7

Frequencies

GnomAD3 genomes

AF:

0.00114

AC:

174

AN:

152250

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000386

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000392

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.0265

Gnomad SAS

AF:

0.00228

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00249

AC:

623

AN:

250466

Hom.:

AF XY:

0.00234

AC XY:

317

AN XY:

135646

show subpopulations

Gnomad AFR exome

AF:

0.000620

Gnomad AMR exome

AF:

0.000116

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0313

Gnomad SAS exome

AF:

0.000948

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000818

GnomAD4 exome

AF:

0.000633

AC:

925

AN:

1460622

Hom.:

Cov.:

AF XY:

0.000636

AC XY:

462

AN XY:

726502

show subpopulations

Gnomad4 AFR exome

AF:

0.000179

Gnomad4 AMR exome

AF:

0.000269

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0182

Gnomad4 SAS exome

AF:

0.000986

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000990

Gnomad4 OTH exome

AF:

0.00142

GnomAD4 genome

AF:

0.00114

AC:

173

AN:

152368

Hom.:

Cov.:

AF XY:

0.00123

AC XY:

AN XY:

74506

show subpopulations

Gnomad4 AFR

AF:

0.000385

Gnomad4 AMR

AF:

0.000392

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.0264

Gnomad4 SAS

AF:

0.00228

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000965

Hom.:

Bravo

AF:

0.00132

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00241

AC:

292

Asia WGS

AF:

0.0130

AC:

AN:

3478

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2023	- -
Benign, 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 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 specified

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Jul 24, 2017

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 24, 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

0.075

BayesDel_addAF

Benign

-0.32

BayesDel_noAF

Benign

-0.20

CADD

Uncertain

DANN

Benign

0.90

DEOGEN2

Uncertain

0.47

T;T

Eigen

Benign

0.13

Eigen_PC

Benign

0.085

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.016

T;T

MetaSVM

Uncertain

-0.27

MutationAssessor

Benign

1.1

L;.

PrimateAI

Uncertain

0.50

PROVEAN

Uncertain

-3.7

D;.

REVEL

Uncertain

0.39

Sift

Benign

0.056

T;.

Sift4G

Benign

0.099

T;T

Polyphen

0.90

P;.

Vest4

0.39

MVP

0.81

MPC

0.12

ClinPred

0.049

GERP RS

4.8

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.37

gMVP

0.55

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