rs572843421
Positions:
Variant summary
Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1
The NM_002906.4(RDX):āc.1282A>Gā(p.Ile428Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000248 in 1,612,860 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).
Frequency
Genomes: š 0.000059 ( 0 hom., cov: 32)
Exomes š: 0.000021 ( 0 hom. )
Consequence
RDX
NM_002906.4 missense
NM_002906.4 missense
Scores
1
5
11
Clinical Significance
Conservation
PhyloP100: 6.18
Genes affected
RDX (HGNC:9944): (radixin) Radixin is a cytoskeletal protein that may be important in linking actin to the plasma membrane. It is highly similar in sequence to both ezrin and moesin. The radixin gene has been localized by fluorescence in situ hybridization to 11q23. A truncated version representing a pseudogene (RDXP2) was assigned to Xp21.3. Another pseudogene that seemed to lack introns (RDXP1) was mapped to 11p by Southern and PCR analyses. Multiple alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.042198867).
BP6
?
Variant 11-110236161-T-C is Benign according to our data. Variant chr11-110236161-T-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 179168.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.0000591 (9/152366) while in subpopulation EAS AF= 0.00135 (7/5186). AF 95% confidence interval is 0.000633. There are 0 homozygotes in gnomad4. There are 4 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RDX | NM_002906.4 | c.1282A>G | p.Ile428Val | missense_variant | 12/14 | ENST00000645495.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RDX | ENST00000645495.2 | c.1282A>G | p.Ile428Val | missense_variant | 12/14 | NM_002906.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000591 AC: 9AN: 152248Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.0000875 AC: 22AN: 251364Hom.: 1 AF XY: 0.0000442 AC XY: 6AN XY: 135860
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GnomAD4 exome AF: 0.0000212 AC: 31AN: 1460494Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726590
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GnomAD4 genome ? AF: 0.0000591 AC: 9AN: 152366Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4AN XY: 74512
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ClinVar
Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:2
Revision: criteria provided, conflicting classifications
LINK: link
Submissions by phenotype
not provided Benign:2
Likely benign, criteria provided, single submitter | clinical testing | Invitae | May 14, 2023 | - - |
Likely benign, criteria provided, single submitter | clinical testing | GeneDx | Oct 22, 2019 | - - |
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Aug 16, 2013 | Variant classified as Uncertain Significance - Favor Benign. The Ile428Val varia nt in RDX has not been previously reported in individuals with hearing loss or i n large population studies. Computational analyses (biochemical amino acid prope rties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Ile428Val variant may not impact the protein, though this information is not predictive en ough to rule out pathogenicity. Of note, fruit fly and C. elegans have a valine (Val) at this position despite high nearby amino acid conservation. In summary, the clinical significance of this variant cannot be determined with certainty; h owever based upon the lack of lower species conservation, and additional computa tion analysis, we would lean towards a more likely benign role. - |
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 03, 2022 | The c.1282A>G (p.I428V) alteration is located in exon 12 (coding exon 11) of the RDX gene. This alteration results from a A to G substitution at nucleotide position 1282, causing the isoleucine (I) at amino acid position 428 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Uncertain
Eigen
Benign
Eigen_PC
Uncertain
FATHMM_MKL
Pathogenic
D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T;T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Benign
L;L;L;.;L;.;L
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N;N;N;.
REVEL
Uncertain
Sift
Benign
T;.;T;T;T;T;.
Sift4G
Benign
T;.;T;T;T;T;.
Polyphen
0.023
.;.;.;.;B;.;B
Vest4
MutPred
Gain of methylation at K427 (P = 0.0871);Gain of methylation at K427 (P = 0.0871);Gain of methylation at K427 (P = 0.0871);.;Gain of methylation at K427 (P = 0.0871);.;Gain of methylation at K427 (P = 0.0871);
MVP
MPC
0.17
ClinPred
T
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at