11-110255294-C-G

Variant names:

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3BP4_ModerateBS1_SupportingBS2

The NM_002906.4(RDX):c.790G>C(p.Ala264Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00016 in 1,521,524 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00016 ( 2 hom. )

Consequence

RDX
NM_002906.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.02

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PP3

Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_noAF, Cadd, MutationAssessor, PrimateAI, PROVEAN, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]

BP4

Computational evidence support a benign effect (MetaRNN=0.18746883).

BS1

Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000145 (22/152122) while in subpopulation SAS AF= 0.00146 (7/4810). AF 95% confidence interval is 0.000683. There are 0 homozygotes in gnomad4. There are 15 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

BS2

High Homozygotes in GnomAdExome4 at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDX	NM_002906.4 link	c.790G>C	p.Ala264Pro	missense_variant	Exon 8 of 14	ENST00000645495.2	NP_002897.1	P35241-1B0YJ88Q6PKD3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2 link	c.790G>C	p.Ala264Pro	missense_variant	Exon 8 of 14		NM_002906.4	ENSP00000496503.2		P35241-1

Frequencies

GnomAD3 genomes

AF:

0.000145

AC:

AN:

152004

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000725

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000655

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00145

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000103

Gnomad OTH

AF:

0.000958

GnomAD3 exomes

AF:

0.000297

AC:

AN:

249290

Hom.:

AF XY:

0.000371

AC XY:

AN XY:

134914

show subpopulations

Gnomad AFR exome

AF:

0.000125

Gnomad AMR exome

AF:

0.000321

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000164

Gnomad SAS exome

AF:

0.00161

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000622

Gnomad OTH exome

AF:

0.000330

GnomAD4 exome

AF:

0.000161

AC:

221

AN:

1369402

Hom.:

Cov.:

AF XY:

0.000194

AC XY:

133

AN XY:

686588

show subpopulations

Gnomad4 AFR exome

AF:

0.0000635

Gnomad4 AMR exome

AF:

0.000270

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000102

Gnomad4 SAS exome

AF:

0.00149

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000593

Gnomad4 OTH exome

AF:

0.000245

GnomAD4 genome

AF:

0.000145

AC:

AN:

152122

Hom.:

Cov.:

AF XY:

0.000202

AC XY:

AN XY:

74362

show subpopulations

Gnomad4 AFR

AF:

0.0000723

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000386

Gnomad4 SAS

AF:

0.00146

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000103

Gnomad4 OTH

AF:

0.000948

Alfa

AF:

0.0000901

Hom.:

Bravo

AF:

0.000121

ESP6500AA

AF:

0.000228

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.000346

AC:

EpiCase

AF:

0.000164

EpiControl

AF:

0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Feb 05, 2015

Variant classified as Uncertain Significance - Favor Benign. The p.Ala264Pro var iant in RDX has not been previously reported in individuals with hearing loss, b ut has been identified in 0.2% (34/15102) of South Asian chromosomes by the Exom e Aggregation Consortium (ExAC, http://exac.broadinstitute.org; dbSNP rs20103165 0). Although this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tool s and conservation analyses do not provide strong support for or against an impa ct to the protein. In summary, while the clinical significance of the p.Ala264Pr o variant is uncertain, these data suggest that it is more likely to be benign. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Uncertain

0.11

BayesDel_noAF

Pathogenic

0.37

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.91

.;.;.;D;.;D

Eigen

Uncertain

0.52

Eigen_PC

Uncertain

0.55

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

.;.;D;.;D;D

M_CAP

Uncertain

0.13

MetaRNN

Benign

0.19

T;T;T;T;T;T

MetaSVM

Uncertain

0.34

MutationAssessor

Pathogenic

3.0

M;M;M;M;.;M

PrimateAI

Pathogenic

0.87

PROVEAN

Pathogenic

-4.9

D;.;D;D;D;.

REVEL

Pathogenic

0.81

Sift

Uncertain

0.0070

D;.;D;D;D;.

Sift4G

Uncertain

0.0060

D;.;D;D;D;.

Polyphen

0.14

.;.;.;B;.;B

Vest4

0.78

MVP

0.93

MPC

0.68

ClinPred

0.24

GERP RS

5.0

Varity_R

0.88

gMVP

0.70

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