rs75639549

Positions:

Variant summary

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

The ENST00000371589.9(MAN1B1):c.1429G>A(p.Gly477Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000942 in 1,553,478 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 Likely benign (★★).

Frequency

Genomes: 𝑓 0.0042 ( 5 hom., cov: 34)

Exomes 𝑓: 0.00059 ( 3 hom. )

Consequence

MAN1B1
ENST00000371589.9 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 7.83

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=0.010476381).

BP6

Variant 9-137106299-G-A is Benign according to our data. Variant chr9-137106299-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 445306.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137106299-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0042 (640/152312) while in subpopulation AFR AF= 0.0144 (599/41570). AF 95% confidence interval is 0.0135. There are 5 homozygotes in gnomad4. There are 297 alleles in male gnomad4 subpopulation. Median coverage is 34. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
MAN1B1	NM_016219.5 linkuse as main transcript	c.1429G>A	p.Gly477Arg	missense_variant	9/13	ENST00000371589.9	NP_057303.2
MAN1B1	XM_006716945.5 linkuse as main transcript	c.1429G>A	p.Gly477Arg	missense_variant	9/12		XP_006717008.1
MAN1B1	NR_045720.2 linkuse as main transcript	n.1444G>A		non_coding_transcript_exon_variant	9/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.1575G>A		non_coding_transcript_exon_variant	10/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.1429G>A	p.Gly477Arg	missense_variant	9/13	1	NM_016219.5	ENSP00000360645	P2

Frequencies

GnomAD3 genomes

AF:

0.00421

AC:

640

AN:

152194

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0144

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00177

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000192

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.0000882

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00107

AC:

170

AN:

159044

Hom.:

AF XY:

0.000901

AC XY:

AN XY:

84320

show subpopulations

Gnomad AFR exome

AF:

0.0146

Gnomad AMR exome

AF:

0.000805

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000130

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000146

Gnomad OTH exome

AF:

0.00112

GnomAD4 exome

AF:

0.000588

AC:

824

AN:

1401166

Hom.:

Cov.:

AF XY:

0.000548

AC XY:

379

AN XY:

691422

show subpopulations

Gnomad4 AFR exome

AF:

0.0167

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.000159

Gnomad4 EAS exome

AF:

0.0000274

Gnomad4 SAS exome

AF:

0.0000879

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000132

Gnomad4 OTH exome

AF:

0.00138

GnomAD4 genome

AF:

0.00420

AC:

640

AN:

152312

Hom.:

Cov.:

AF XY:

0.00399

AC XY:

297

AN XY:

74472

show subpopulations

Gnomad4 AFR

AF:

0.0144

Gnomad4 AMR

AF:

0.00176

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000882

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000733

Hom.:

Bravo

AF:

0.00478

ESP6500AA

AF:

0.0109

AC:

ESP6500EA

AF:

0.000119

AC:

ExAC

AF:

0.000946

AC:

103

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 15, 2017	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	MAN1B1: BS1, BS2 -

Rafiq syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 25, 2024

- -

Inborn genetic diseases

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 08, 2019

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. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Benign

-0.035

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.62

D;D

Eigen

Uncertain

0.44

Eigen_PC

Uncertain

0.43

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.96

D;D

MetaRNN

Benign

0.010

T;T

MetaSVM

Uncertain

0.041

MutationAssessor

Pathogenic

2.9

M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.50

PROVEAN

Pathogenic

-5.6

D;.

REVEL

Pathogenic

0.77

Sift

Uncertain

0.0020

D;.

Sift4G

Uncertain

0.0040

D;D

Polyphen

1.0

D;.

Vest4

0.68

MutPred

0.56

Gain of solvent accessibility (P = 0.0014);.;

MVP

0.96

MPC

0.47

ClinPred

0.030

GERP RS

4.1

Varity_R

0.77

gMVP

0.77

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