chr11-110236134-TC-T

Variant names:

• chr11-110236134-TC-T
• rs727504709
• NM_002906.4:c.1308delG

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_002906.4(RDX):​c.1308delG​(p.Lys438ArgfsTer26) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RDX NM_002906.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 2.77
• Publications: 1 publications found

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

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 11-110236134-TC-T is Pathogenic according to our data. Variant chr11-110236134-TC-T is described in ClinVar as Pathogenic. ClinVar VariationId is 179207.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002906.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDX	NM_002906.4	MANE Select	c.1308delG	p.Lys438ArgfsTer26	frameshift	Exon 12 of 14	NP_002897.1
	RDX	NM_001440509.1		c.1494delG	p.Lys500ArgfsTer26	frameshift	Exon 13 of 15	NP_001427438.1
	RDX	NM_001260492.2		c.1308delG	p.Lys438ArgfsTer26	frameshift	Exon 12 of 16	NP_001247421.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDX	ENST00000645495.2	MANE Select	c.1308delG	p.Lys438ArgfsTer26	frameshift	Exon 12 of 14	ENSP00000496503.2
	RDX	ENST00000528498.5	TSL:1	c.1308delG	p.Lys438ArgfsTer26	frameshift	Exon 12 of 16	ENSP00000432112.1
	RDX	ENST00000528900.5	TSL:1	c.267delG	p.Lys91ArgfsTer26	frameshift	Exon 5 of 9	ENSP00000433580.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Rare genetic deafness Pathogenic:1

Sep 07, 2013

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The Lys438fs variant in RDX has not been reported in individuals with hearing lo ss or in large population studies. This frameshift variant is predicted to alter the protein?s amino acid sequence beginning at position 438 and lead to a prema ture termination codon 26 amino acids downstream. This alteration is then predic ted to lead to a truncated or absent protein. Loss of function variants in the RDX gene have been reported in other individuals with hearing loss, suggesting t hat the pathogenic mechanism is due to loss of the RDX gene product (Khan 2007). In summary, this variant meets our criteria to be classified as pathogenic (htt p://pcpgm.partners.org/LMM).

Autosomal recessive nonsyndromic hearing loss 24 Pathogenic:1

Sep 22, 2024

Genomic Medicine Center of Excellence, King Faisal Specialist Hospital and Research Centre

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.8
Mutation Taster		=0/200	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs727504709; hg19: chr11-110106859;