rs118117962

Positions:

chr9-137108543-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_016219.5(MAN1B1):c.2052C>T(p.Tyr684Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0365 in 1,613,800 control chromosomes in the GnomAD database, including 1,258 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 95 hom., cov: 32)

Exomes 𝑓: 0.037 ( 1163 hom. )

Consequence

MAN1B1
NM_016219.5 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -1.75

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.8).

BP6

Variant 9-137108543-C-T is Benign according to our data. Variant chr9-137108543-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 129578.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=-1.75 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0289 (4397/152298) while in subpopulation NFE AF= 0.0418 (2845/68020). AF 95% confidence interval is 0.0405. There are 95 homozygotes in gnomad4. There are 2092 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAN1B1	NM_016219.5 linkuse as main transcript	c.2052C>T	p.Tyr684Tyr	synonymous_variant	13/13	ENST00000371589.9	NP_057303.2	Q9UKM7
MAN1B1	NR_045720.2 linkuse as main transcript	n.2042C>T		non_coding_transcript_exon_variant	13/13
MAN1B1	NR_045721.2 linkuse as main transcript	n.2198C>T		non_coding_transcript_exon_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAN1B1	ENST00000371589.9 linkuse as main transcript	c.2052C>T	p.Tyr684Tyr	synonymous_variant	13/13	1	NM_016219.5	ENSP00000360645.4		Q9UKM7

Frequencies

GnomAD3 genomes

AF:

0.0289

AC:

4397

AN:

152180

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00719

Gnomad AMI

AF:

0.0680

Gnomad AMR

AF:

0.0299

Gnomad ASJ

AF:

0.0714

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.0205

Gnomad FIN

AF:

0.0288

Gnomad MID

AF:

0.0222

Gnomad NFE

AF:

0.0418

Gnomad OTH

AF:

0.0301

GnomAD3 exomes

AF:

0.0302

AC:

7598

AN:

251480

Hom.:

167

AF XY:

0.0311

AC XY:

4227

AN XY:

135914

show subpopulations

Gnomad AFR exome

AF:

0.00566

Gnomad AMR exome

AF:

0.0183

Gnomad ASJ exome

AF:

0.0687

Gnomad EAS exome

AF:

0.000163

Gnomad SAS exome

AF:

0.0206

Gnomad FIN exome

AF:

0.0263

Gnomad NFE exome

AF:

0.0418

Gnomad OTH exome

AF:

0.0366

GnomAD4 exome

AF:

0.0373

AC:

54570

AN:

1461502

Hom.:

1163

Cov.:

AF XY:

0.0370

AC XY:

26920

AN XY:

727054

show subpopulations

Gnomad4 AFR exome

AF:

0.00535

Gnomad4 AMR exome

AF:

0.0186

Gnomad4 ASJ exome

AF:

0.0687

Gnomad4 EAS exome

AF:

0.000151

Gnomad4 SAS exome

AF:

0.0214

Gnomad4 FIN exome

AF:

0.0279

Gnomad4 NFE exome

AF:

0.0415

Gnomad4 OTH exome

AF:

0.0342

GnomAD4 genome

AF:

0.0289

AC:

4397

AN:

152298

Hom.:

Cov.:

AF XY:

0.0281

AC XY:

2092

AN XY:

74462

show subpopulations

Gnomad4 AFR

AF:

0.00717

Gnomad4 AMR

AF:

0.0299

Gnomad4 ASJ

AF:

0.0714

Gnomad4 EAS

AF:

0.00231

Gnomad4 SAS

AF:

0.0207

Gnomad4 FIN

AF:

0.0288

Gnomad4 NFE

AF:

0.0418

Gnomad4 OTH

AF:

0.0298

Alfa

AF:

0.0381

Hom.:

Bravo

AF:

0.0285

Asia WGS

AF:

0.00866

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Rafiq syndrome

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 14, 2020	- -
Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 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

BayesDel_noAF

Benign

-0.80

CADD

Benign

0.65

DANN

Benign

0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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