11-110255294-C-G

Position:

• chr11-110255294-C-G

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP3 BP4_Moderate BS1_Supporting BS2

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.02

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 (HGNC:):

ACMG classification

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/exons	MANE	Protein	UniProt
RDX	NM_002906.4	c.790G>C	p.Ala264Pro	missense_variant	8/14	ENST00000645495.2	NP_002897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2	c.790G>C	p.Ala264Pro	missense_variant	8/14		NM_002906.4	ENSP00000496503.2

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152004 Hom.: 0 Cov.: 32

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: 74 AN: 249290 Hom.: 0 AF XY: 0.000371 AC XY: 50 AN XY: 134914

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.: 2 Cov.: 24 AF XY: 0.000194 AC XY: 133 AN XY: 686588

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: 22 AN: 152122 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74362

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.: 0

Bravo AF: 0.000121

ESP6500AA AF: 0.000228 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000346 AC: 42

EpiCase AF: 0.000164

EpiControl AF: 0.000178

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Pathogenic	0.37
CADD	Pathogenic	30
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.91	.;.;.;D;.;D
Eigen	Uncertain	0.52
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	.;.;D;.;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.19	T;T;T;T;T;T
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.0	M;M;M;M;.;M
PrimateAI	Pathogenic	0.87	D
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	T
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

Other links and lift over

dbSNP: rs201031650; hg19: chr11-110126019;