chr11-110233356-C-T

Position:

chr11-110233356-C-T

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM2BP4_StrongBP6BS1

The NM_002906.4(RDX):c.1468G>A(p.Asp490Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000159 in 1,614,150 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). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.00082 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000090 ( 0 hom. )

Consequence

RDX
NM_002906.4 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: 4.74

Variant links:

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]

RDX links:

RDX (HGNC:):

RDX links:

Genome browser will be placed here

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=0.019935489).

BP6

Variant 11-110233356-C-T is Benign according to our data. Variant chr11-110233356-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44637.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000821 (125/152282) while in subpopulation AFR AF= 0.00279 (116/41564). AF 95% confidence interval is 0.00238. There are 0 homozygotes in gnomad4. There are 61 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	Protein	UniProt
RDX	NM_002906.4 linkuse as main transcript	c.1468G>A	p.Asp490Asn	missense_variant	13/14	ENST00000645495.2	NP_002897.1	P35241-1B0YJ88Q6PKD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2 linkuse as main transcript	c.1468G>A	p.Asp490Asn	missense_variant	13/14		NM_002906.4	ENSP00000496503.2		P35241-1

Frequencies

GnomAD3 genomes

AF:

0.000821

AC:

125

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00280

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000327

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000199

AC:

AN:

251474

Hom.:

AF XY:

0.000155

AC XY:

AN XY:

135912

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000791

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000896

AC:

131

AN:

1461868

Hom.:

Cov.:

AF XY:

0.0000825

AC XY:

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00299

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000243

Gnomad4 OTH exome

AF:

0.0000662

GnomAD4 genome

AF:

0.000821

AC:

125

AN:

152282

Hom.:

Cov.:

AF XY:

0.000819

AC XY:

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00279

Gnomad4 AMR

AF:

0.000327

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000186

Hom.:

Bravo

AF:

0.000869

ESP6500AA

AF:

0.00227

AC:

ESP6500EA

AF:

0.000233

AC:

ExAC

AF:

0.000255

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 10, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2019	- -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 31, 2021

Variant classified as Uncertain Significance - Favor Benign. The p.Asp490Asn variant in RDX has been reported in the heterozygous state in 2 individuals with hearing loss (LMM data), but has also been identified in 0.24% (62/24972) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). Computational prediction tools and conservation analysis do not provide strong support for or against an impact to the protein. In summary, while the clinical significance of this variant is uncertain, its frequency suggests it is more likely to be benign. ACMG/AMP Criteria applied: BS1_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.17

BayesDel_addAF

Benign

-0.38

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.51

.;.;.;.;D;.;D

Eigen

Uncertain

0.26

Eigen_PC

Uncertain

0.39

FATHMM_MKL

Uncertain

0.94

LIST_S2

Pathogenic

0.98

.;.;D;D;.;D;D

M_CAP

Benign

0.034

MetaRNN

Benign

0.020

T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.3

M;M;M;.;M;.;M

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-1.8

N;.;N;N;N;N;.

REVEL

Uncertain

0.36

Sift

Benign

0.22

T;.;T;D;T;T;.

Sift4G

Benign

0.17

T;.;T;T;T;T;.

Polyphen

0.21

.;.;.;.;B;.;B

Vest4

0.35

MVP

0.82

MPC

0.18

ClinPred

0.043

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.13

gMVP

0.69

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over