rs74983220

Positions:

• chr11-110233337-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_002906.4(RDX):​c.1487C>T​(p.Ala496Val) variant causes a missense change. The variant allele was found at a frequency of 0.0023 in 1,614,118 control chromosomes in the GnomAD database, including 13 homozygotes. 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: 𝑓 0.0016 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (13 hom.)
• Consequence: RDX NM_002906.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 4.28

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.009947151).
• BP6: Variant 11-110233337-G-A is Benign according to our data. Variant chr11-110233337-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 44638.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Benign=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00164 (250/152256) while in subpopulation NFE AF= 0.00279 (190/68038). AF 95% confidence interval is 0.00247. There are 0 homozygotes in gnomad4. There are 107 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RDX	NM_002906.4	c.1487C>T	p.Ala496Val	missense_variant	13/14	ENST00000645495.2	NP_002897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2	c.1487C>T	p.Ala496Val	missense_variant	13/14		NM_002906.4	ENSP00000496503	P1

Frequencies

GnomAD3 genomes AF: 0.00164 AC: 250 AN: 152138 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000362

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00144

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00179

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00279

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00186 AC: 469 AN: 251482 Hom.: 1 AF XY: 0.00183 AC XY: 249 AN XY: 135914

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00226

Gnomad NFE exome AF: 0.00327

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00237 AC: 3461 AN: 1461862 Hom.: 13 Cov.: 33 AF XY: 0.00221 AC XY: 1609 AN XY: 727232

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000738

Gnomad4 ASJ exome AF: 0.000191

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00322

Gnomad4 NFE exome AF: 0.00278

Gnomad4 OTH exome AF: 0.00243

GnomAD4 genome AF: 0.00164 AC: 250 AN: 152256 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74442

Gnomad4 AFR AF: 0.000361

Gnomad4 AMR AF: 0.00144

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00179

Gnomad4 NFE AF: 0.00279

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00251 Hom.: 1

Bravo AF: 0.00158

TwinsUK AF: 0.00162 AC: 6

ALSPAC AF: 0.00285 AC: 11

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00244 AC: 21

ExAC AF: 0.00231 AC: 280

EpiCase AF: 0.00273

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Jul 03, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	RDX: BS2 -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 29, 2019	This variant is associated with the following publications: (PMID: 27231709) -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 02, 2024	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jun 06, 2017	p.Ala496Val in exon 13 of RDX: This variant is not expected to have clinical sig nificance because it has been identified in 0.3% (411/126718) of European chromo somes including one homozygote by the Genome Aggregation Database (gnomAD, http: //gnomad.broadinstitute.org; dbSNP rs74983220). -
Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 04, 2015	- -

Autosomal recessive nonsyndromic hearing loss 24 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 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. -

RDX-related disorder Benign:1

Likely benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 26, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	.;.;.;.;T;.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.97	.;.;D;D;.;D;D
M_CAP	Benign	0.068	D
MetaRNN	Benign	0.0099	T;T;T;T;T;T;T
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Uncertain	2.0	M;M;M;.;M;.;M
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.62	T
PROVEAN	Benign	-0.15	N;.;N;N;N;N;.
REVEL	Uncertain	0.36
Sift	Benign	0.54	T;.;T;T;T;T;.
Sift4G	Benign	0.53	T;.;T;T;T;T;.
Polyphen		0.76	.;.;.;.;P;.;P
Vest4		0.59
MVP		0.63
MPC		0.33
ClinPred		0.078	T
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.063
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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

Other links and lift over

dbSNP: rs74983220; hg19: chr11-110104062;