4-102632067-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005908.4(MANBA):c.2630A>G(p.Asp877Gly) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: MANBA NM_005908.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.05

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MANBA	NM_005908.4	c.2630A>G	p.Asp877Gly	missense_variant	17/17	ENST00000647097.2
MANBA	XM_047415692.1	c.2555A>G	p.Asp852Gly	missense_variant	18/18
MANBA	XM_047415693.1	c.2555A>G	p.Asp852Gly	missense_variant	18/18
MANBA	XM_047415694.1	c.1982A>G	p.Asp661Gly	missense_variant	13/13

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MANBA	ENST00000647097.2	c.2630A>G	p.Asp877Gly	missense_variant	17/17		NM_005908.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

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

Invitae

Nov 14, 2020

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals with MANBA-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces aspartic acid with glycine at codon 877 of the MANBA protein (p.Asp877Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
Cadd	Benign	21
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.78	D;D;.;.
Eigen	Uncertain	0.24
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.70	D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.9	M;M;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Pathogenic	-4.7	D;.;.;D
REVEL	Uncertain	0.59
Sift	Benign	0.13	T;.;.;T
Sift4G	Uncertain	0.014	D;.;.;D
Polyphen		0.34	B;B;.;D
Vest4		0.69
MutPred		0.48		Gain of glycosylation at Y879 (P = 0.0557);Gain of glycosylation at Y879 (P = 0.0557);.;.;
MVP		0.79
MPC		0.42
ClinPred		0.99	D
GERP RS		5.1
Varity_R		0.57
gMVP		0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs752396515; hg19: chr4-103553224;