Genetic Variant MAN1B1:p.Arg188Ser (chr9-137096335-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_016219.5(MAN1B1):c.564G>T(p.Arg188Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R188R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

MAN1B1
NM_016219.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.203

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: ClinGen, Orphanet
Rafiq syndrome
Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MAN1B1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.09168202).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_016219.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAN1B1	NM_016219.5	MANE Select	c.564G>T	p.Arg188Ser	missense	Exon 4 of 13	NP_057303.2	Q9UKM7
MAN1B1	NR_045720.2		n.579G>T		non_coding_transcript_exon	Exon 4 of 13
MAN1B1	NR_045721.2		n.710G>T		non_coding_transcript_exon	Exon 5 of 14

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MAN1B1	ENST00000371589.9	TSL:1 MANE Select	c.564G>T	p.Arg188Ser	missense	Exon 4 of 13	ENSP00000360645.4	Q9UKM7
MAN1B1	ENST00000371587.9	TSL:1	n.*266G>T		non_coding_transcript_exon	Exon 5 of 14	ENSP00000483132.2	A0A087X064
MAN1B1	ENST00000544448.6	TSL:1	n.564G>T		non_coding_transcript_exon	Exon 4 of 13	ENSP00000444966.2	H0YGV7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.055

BayesDel_noAF

Benign

-0.32

CADD

Benign

8.6

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.021

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.84

FATHMM_MKL

Benign

0.085

LIST_S2

Benign

0.57

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.092

MetaSVM

Benign

-0.88

MutationAssessor

Benign

1.6

PhyloP100

0.20

PrimateAI

Benign

0.28

PROVEAN

Benign

-1.4

REVEL

Benign

0.14

Sift

Benign

0.22

Sift4G

Benign

0.63

Polyphen

0.11

Vest4

0.19

MutPred

0.18

Gain of phosphorylation at R188 (P = 0.0143)

MVP

0.64

MPC

0.099

ClinPred

0.043

GERP RS

2.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.074

gMVP

0.26

Mutation Taster

=89/11

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over