rs727503393

Variant names:

• chr11-110236102-G-T
• rs727503393
• NM_002906.4:c.1341C>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Moderate BP6_Moderate

The NM_002906.4(RDX):​c.1341C>A​(p.His447Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000138 in 1,452,848 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RDX NM_002906.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.28
• Publications: 0 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.098231286).
• BP6: Variant 11-110236102-G-T is Benign according to our data. Variant chr11-110236102-G-T is described in ClinVar as Likely_benign. ClinVar VariationId is 165052.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RDX	NM_002906.4	c.1341C>A	p.His447Gln	missense_variant	Exon 12 of 14	ENST00000645495.2	NP_002897.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RDX	ENST00000645495.2	c.1341C>A	p.His447Gln	missense_variant	Exon 12 of 14		NM_002906.4	ENSP00000496503.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1452848 Hom.: 0 Cov.: 29 AF XY: 0.00000138 AC XY: 1 AN XY: 723358

African (AFR) AF: 0.00 AC: 0 AN: 33270

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26086

East Asian (EAS) AF: 0.00 AC: 0 AN: 39612

South Asian (SAS) AF: 0.00 AC: 0 AN: 86034

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53372

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4150

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1105640

Other (OTH) AF: 0.00 AC: 0 AN: 59970

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Jul 17, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

His447Gln in exon 12 of RDX: This variant is not expected to have clinical signi ficance due to a lack of conservation across species, including mammals. Of note , several bat species as well as other distant species have a glutamine (Gln) at this position, suggesting that this change can be tolerated. In addition, compu tational prediction tools suggest that the His447Gln variant may not impact the protein. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.33
DEOGEN2	Benign	0.23	.;.;.;.;T;.;T
Eigen	Benign	-0.85
Eigen_PC	Benign	-0.66
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.75	.;.;T;T;.;T;T
M_CAP	Benign	0.036	D
MetaRNN	Benign	0.098	T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	-0.72	N;N;N;.;N;.;N
PhyloP100		1.3
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	0.19	N;.;N;N;N;N;.
REVEL	Benign	0.026
Sift	Benign	1.0	T;.;T;T;T;T;.
Sift4G	Benign	0.68	T;.;T;T;T;T;.
Polyphen		0.0	.;.;.;.;B;.;B
Vest4		0.29
MutPred		0.46		Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);Gain of solvent accessibility (P = 0.0374);.;Gain of solvent accessibility (P = 0.0374);.;Gain of solvent accessibility (P = 0.0374);
MVP		0.42
MPC		0.16
ClinPred		0.075	T
GERP RS		2.1
Varity_R		0.033
gMVP		0.79
Mutation Taster		=70/26	polymorphism

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: rs727503393; hg19: chr11-110106827;