rs139953187

Variant names:

• chr11-110247734-T-C
• rs139953187
• NM_002906.4:c.1059A>G

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_002906.4(RDX):​c.1059A>G​(p.Gln353Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0013 in 1,612,290 control chromosomes in the GnomAD database, including 20 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 0.0064 (12 hom., cov: 32)
  • Exomes 𝑓: 0.00077 (8 hom.)
• Consequence: RDX NM_002906.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.64
• 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 11-110247734-T-C is Benign according to our data. Variant chr11-110247734-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 44636.
• BP7: Synonymous conserved (PhyloP=2.64 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00636 (969/152330) while in subpopulation AFR AF = 0.021 (874/41578). AF 95% confidence interval is 0.0199. There are 12 homozygotes in GnomAd4. There are 455 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 12 AR gene

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDX	NM_002906.4	MANE Select	c.1059A>G	p.Gln353Gln	synonymous	Exon 10 of 14	NP_002897.1	B0YJ88
	RDX	NM_001440509.1		c.1059A>G	p.Gln353Gln	synonymous	Exon 10 of 15	NP_001427438.1
	RDX	NM_001260492.2		c.1059A>G	p.Gln353Gln	synonymous	Exon 10 of 16	NP_001247421.1	P35241-5

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RDX	ENST00000645495.2	MANE Select	c.1059A>G	p.Gln353Gln	synonymous	Exon 10 of 14	ENSP00000496503.2	P35241-1
	RDX	ENST00000528498.5	TSL:1	c.1059A>G	p.Gln353Gln	synonymous	Exon 10 of 16	ENSP00000432112.1	P35241-5
	RDX	ENST00000528900.5	TSL:1	c.18A>G	p.Gln6Gln	synonymous	Exon 3 of 9	ENSP00000433580.1	P35241-2

Frequencies

GnomAD3 genomes AF: 0.00633 AC: 964 AN: 152214 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0209

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00517

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00334

GnomAD2 exomes AF: 0.00196 AC: 484 AN: 246916 AF XY: 0.00140

Gnomad AFR exome AF: 0.0230

Gnomad AMR exome AF: 0.00218

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000226

Gnomad OTH exome AF: 0.00164

GnomAD4 exome AF: 0.000771 AC: 1126 AN: 1459960 Hom.: 8 Cov.: 31 AF XY: 0.000654 AC XY: 475 AN XY: 726254

African (AFR) AF: 0.0219 AC: 732 AN: 33418

American (AMR) AF: 0.00292 AC: 130 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26102

East Asian (EAS) AF: 0.00 AC: 0 AN: 39584

South Asian (SAS) AF: 0.0000698 AC: 6 AN: 85930

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52714

Middle Eastern (MID) AF: 0.00157 AC: 9 AN: 5744

European-Non Finnish (NFE) AF: 0.000130 AC: 145 AN: 1111540

Other (OTH) AF: 0.00172 AC: 104 AN: 60342

GnomAD4 genome AF: 0.00636 AC: 969 AN: 152330 Hom.: 12 Cov.: 32 AF XY: 0.00611 AC XY: 455 AN XY: 74492

African (AFR) AF: 0.0210 AC: 874 AN: 41578

American (AMR) AF: 0.00510 AC: 78 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5190

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10622

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68014

Other (OTH) AF: 0.00331 AC: 7 AN: 2116

Alfa AF: 0.00342 Hom.: 3

Bravo AF: 0.00732

Asia WGS AF: 0.00145 AC: 5 AN: 3474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	1	-	Autosomal recessive nonsyndromic hearing loss 24 (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	3.8
DANN	Benign	0.43
PhyloP100		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=96/4	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: rs139953187; hg19: chr11-110118459;