Genetic Variant RDX:p.Ala264Thr (chr11-110255294-C-T) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_002906.4(RDX):c.790G>A(p.Ala264Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000365 in 1,369,408 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A264P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000037 ( 1 hom. )

Consequence

RDX
NM_002906.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.02

Publications

2 publications found

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 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 24
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

RDX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDX	NM_002906.4 link	c.790G>A	p.Ala264Thr	missense_variant	Exon 8 of 14	ENST00000645495.2	NP_002897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2 link	c.790G>A	p.Ala264Thr	missense_variant	Exon 8 of 14		NM_002906.4	ENSP00000496503.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000365

AC:

AN:

1369408

Hom.:

Cov.:

AF XY:

0.00000583

AC XY:

AN XY:

686592

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31492

American (AMR)

AF:

0.00

AC:

AN:

44402

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25534

East Asian (EAS)

AF:

0.00

AC:

AN:

39080

South Asian (SAS)

AF:

0.00

AC:

AN:

84174

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53290

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4964

European-Non Finnish (NFE)

AF:

0.00000486

AC:

AN:

1029224

Other (OTH)

AF:

0.00

AC:

AN:

57248

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.88

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.89

.;.;.;D;.;D

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.37

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Benign

0.78

.;.;T;.;T;T

M_CAP

Benign

0.075

MetaRNN

Uncertain

0.66

D;D;D;D;D;D

MetaSVM

Uncertain

0.060

MutationAssessor

Uncertain

2.1

M;M;M;M;.;M

PhyloP100

6.0

PrimateAI

Pathogenic

0.84

PROVEAN

Uncertain

-3.9

D;.;D;D;D;.

REVEL

Uncertain

0.63

Sift

Uncertain

0.0060

D;.;D;D;D;.

Sift4G

Benign

0.061

T;.;T;T;D;.

Polyphen

0.0030

.;.;.;B;.;B

Vest4

0.73

MutPred

0.39

Gain of phosphorylation at A264 (P = 0.0219);Gain of phosphorylation at A264 (P = 0.0219);Gain of phosphorylation at A264 (P = 0.0219);Gain of phosphorylation at A264 (P = 0.0219);.;Gain of phosphorylation at A264 (P = 0.0219);

MVP

0.89

MPC

0.22

ClinPred

0.99

GERP RS

5.0

Varity_R

0.60

gMVP

0.45

Mutation Taster

=25/75

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over