rs1553951373

Positions:

• chr4-102714521-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_005908.4(MANBA):​c.590C>G​(p.Pro197Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 8.40

Genes affected

MANBA (HGNC:6831): (mannosidase beta) This gene encodes a member of the glycosyl hydrolase 2 family. The encoded protein localizes to the lysosome where it is the final exoglycosidase in the pathway for N-linked glycoprotein oligosaccharide catabolism. Mutations in this gene are associated with beta-mannosidosis, a lysosomal storage disease that has a wide spectrum of neurological involvement. [provided by RefSeq, Jul 2008]

MANBA (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.882

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MANBA	NM_005908.4	c.590C>G	p.Pro197Arg	missense_variant	5/17	ENST00000647097.2	NP_005899.3
MANBA	XM_047415692.1	c.515C>G	p.Pro172Arg	missense_variant	6/18		XP_047271648.1
MANBA	XM_047415693.1	c.515C>G	p.Pro172Arg	missense_variant	6/18		XP_047271649.1
MANBA	XM_047415694.1	c.25+8350C>G		intron_variant			XP_047271650.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MANBA	ENST00000647097.2	c.590C>G	p.Pro197Arg	missense_variant	5/17		NM_005908.4	ENSP00000495247.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Beta-D-mannosidosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 03, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.83
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	.;D;D;.;.;.
Eigen	Pathogenic	0.83
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D;.;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D
MetaSVM	Uncertain	0.36	D
MutationAssessor	Uncertain	2.6	.;M;M;.;.;.
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-7.0	.;D;.;.;D;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	.;D;.;.;D;.
Sift4G	Uncertain	0.0060	.;D;.;.;D;.
Polyphen		1.0	.;D;D;.;D;.
Vest4		0.88, 0.88
MutPred		0.67		Gain of catalytic residue at P197 (P = 0.0474);Gain of catalytic residue at P197 (P = 0.0474);Gain of catalytic residue at P197 (P = 0.0474);Gain of catalytic residue at P197 (P = 0.0474);.;.;
MVP		0.89
MPC		0.45
ClinPred		0.99	D
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.86

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: rs1553951373; hg19: chr4-103635678;