rs118117962

chr9-137108543-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_016219.5(MAN1B1):c.2052C>T(p.Tyr684=) 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
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.75

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]

ACMG classification

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. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 95 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1B1	NM_016219.5	c.2052C>T	p.Tyr684=	synonymous_variant	13/13	ENST00000371589.9
MAN1B1	NR_045720.2	n.2042C>T		non_coding_transcript_exon_variant	13/13
MAN1B1	NR_045721.2	n.2198C>T		non_coding_transcript_exon_variant	14/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9	c.2052C>T	p.Tyr684=	synonymous_variant	13/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes AF: 0.0289 AC: 4397 AN: 152180 Hom.: 95 Cov.: 32

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

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.: 35 AF XY: 0.0370 AC XY: 26920 AN XY: 727054

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.: 95 Cov.: 32 AF XY: 0.0281 AC XY: 2092 AN XY: 74462

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.: 56

Bravo AF: 0.0285

Asia WGS AF: 0.00866 AC: 30 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

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	Invitae	Jan 31, 2024	- -

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. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Feb 14, 2020

- -

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

Other links and lift over

dbSNP: rs118117962; hg19: chr9-140002995; COSMIC: COSV65370916; COSMIC: COSV65370916;