rs147428514
Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005908.4(MANBA):c.2296C>T(p.Arg766Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000129 in 1,614,196 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. R766R) has been classified as Likely benign.
Frequency
Consequence
NM_005908.4 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Uncertain_significance. Variant got 2 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
MANBA | NM_005908.4 | c.2296C>T | p.Arg766Trp | missense_variant | 16/17 | ENST00000647097.2 | |
MANBA | XM_047415692.1 | c.2221C>T | p.Arg741Trp | missense_variant | 17/18 | ||
MANBA | XM_047415693.1 | c.2221C>T | p.Arg741Trp | missense_variant | 17/18 | ||
MANBA | XM_047415694.1 | c.1648C>T | p.Arg550Trp | missense_variant | 12/13 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
MANBA | ENST00000647097.2 | c.2296C>T | p.Arg766Trp | missense_variant | 16/17 | NM_005908.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000269 AC: 41AN: 152194Hom.: 0 Cov.: 33
GnomAD3 exomes AF: 0.000211 AC: 53AN: 251356Hom.: 0 AF XY: 0.000258 AC XY: 35AN XY: 135858
GnomAD4 exome AF: 0.000114 AC: 167AN: 1461884Hom.: 0 Cov.: 34 AF XY: 0.000121 AC XY: 88AN XY: 727242
GnomAD4 genome ? AF: 0.000269 AC: 41AN: 152312Hom.: 0 Cov.: 33 AF XY: 0.000242 AC XY: 18AN XY: 74472
ClinVar
Submissions by phenotype
Beta-D-mannosidosis Uncertain:4
Uncertain significance, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center | Mar 25, 2024 | - - |
Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 20, 2022 | This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 766 of the MANBA protein (p.Arg766Trp). This variant is present in population databases (rs147428514, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with MANBA-related conditions. ClinVar contains an entry for this variant (Variation ID: 347083). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MANBA protein function. 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. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 31, 2018 | - - |
not provided Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Apr 20, 2022 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge - |
Uncertain significance, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | May 01, 2017 | - - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 11, 2022 | The c.2296C>T (p.R766W) alteration is located in exon 16 (coding exon 16) of the MANBA gene. This alteration results from a C to T substitution at nucleotide position 2296, causing the arginine (R) at amino acid position 766 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at