rs61744585

chr9-137096361-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_016219.5(MAN1B1):c.590C>T(p.Pro197Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0195 in 1,613,756 control chromosomes in the GnomAD database, including 1,145 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P197A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.019 (96 hom., cov: 32)
  • Exomes 𝑓: 0.019 (1049 hom.)
• Consequence: MAN1B1 NM_016219.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.360

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0012768805).
• BP6: Variant 9-137096361-C-T is Benign according to our data. Variant chr9-137096361-C-T is described in ClinVar as [Benign]. Clinvar id is 129580.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-137096361-C-T is described in Lovd as [Likely_benign].
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.0921 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MAN1B1	NM_016219.5	c.590C>T	p.Pro197Leu	missense_variant	4/13	ENST00000371589.9
MAN1B1	XM_006716945.5	c.590C>T	p.Pro197Leu	missense_variant	4/12
MAN1B1	NR_045720.2	n.605C>T		non_coding_transcript_exon_variant	4/13
MAN1B1	NR_045721.2	n.736C>T		non_coding_transcript_exon_variant	5/14

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MAN1B1	ENST00000371589.9	c.590C>T	p.Pro197Leu	missense_variant	4/13	1	NM_016219.5	P2

Frequencies

GnomAD3 genomes AF: 0.0192 AC: 2927 AN: 152216 Hom.: 95 Cov.: 32

Gnomad AFR AF: 0.00485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0958

Gnomad ASJ AF: 0.0199

Gnomad EAS AF: 0.000577

Gnomad SAS AF: 0.0186

Gnomad FIN AF: 0.00518

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.0201

GnomAD3 exomes AF: 0.0374 AC: 9355 AN: 250174 Hom.: 785 AF XY: 0.0312 AC XY: 4231 AN XY: 135506

Gnomad AFR exome AF: 0.00520

Gnomad AMR exome AF: 0.194

Gnomad ASJ exome AF: 0.0186

Gnomad EAS exome AF: 0.000272

Gnomad SAS exome AF: 0.0179

Gnomad FIN exome AF: 0.00643

Gnomad NFE exome AF: 0.0136

Gnomad OTH exome AF: 0.0259

GnomAD4 exome AF: 0.0195 AC: 28482 AN: 1461422 Hom.: 1049 Cov.: 32 AF XY: 0.0187 AC XY: 13628 AN XY: 726976

Gnomad4 AFR exome AF: 0.00400

Gnomad4 AMR exome AF: 0.180

Gnomad4 ASJ exome AF: 0.0205

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.0183

Gnomad4 FIN exome AF: 0.00702

Gnomad4 NFE exome AF: 0.0151

Gnomad4 OTH exome AF: 0.0162

GnomAD4 genome AF: 0.0193 AC: 2933 AN: 152334 Hom.: 96 Cov.: 32 AF XY: 0.0203 AC XY: 1513 AN XY: 74478

Gnomad4 AFR AF: 0.00483

Gnomad4 AMR AF: 0.0961

Gnomad4 ASJ AF: 0.0199

Gnomad4 EAS AF: 0.000579

Gnomad4 SAS AF: 0.0186

Gnomad4 FIN AF: 0.00518

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.0198

Alfa AF: 0.0147 Hom.: 23

Bravo AF: 0.0278

TwinsUK AF: 0.0121 AC: 45

ALSPAC AF: 0.0127 AC: 49

ESP6500AA AF: 0.00590 AC: 26

ESP6500EA AF: 0.0135 AC: 116

ExAC AF: 0.0311 AC: 3775

Asia WGS AF: 0.0120 AC: 43 AN: 3478

EpiCase AF: 0.0125

EpiControl AF: 0.0132

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 14, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	May 05, 2015	- -

Rafiq syndrome Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 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

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 12, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.46
Cadd	Benign	0.42
Dann	Benign	0.89
DEOGEN2	Benign	0.023	T;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.051	N
LIST_S2	Benign	0.59	T;T
MetaRNN	Benign	0.0013	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.1	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.24	T
PROVEAN	Benign	-1.1	N;.
REVEL	Benign	0.060
Sift	Benign	0.098	T;.
Sift4G	Benign	0.31	T;T
Polyphen		0.59	P;.
Vest4		0.069
MPC		0.087
ClinPred		0.0032	T
GERP RS		-3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.026
gMVP		0.15

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: rs61744585; hg19: chr9-139990813; COSMIC: COSV63034911; COSMIC: COSV63034911;