rs144543614

Variant names:

• chr11-110264073-C-A
• rs144543614
• NM_002906.4:c.354G>T

Your query was ambiguous. Multiple possible variants found:

• chr11-110264073-C-A
• chr11-110264073-C-T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Moderate BP6 BP7 BS1 BS2

The NM_002906.4(RDX):​c.354G>T​(p.Pro118Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000376 in 1,613,698 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P118P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00049 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (5 hom.)
• Consequence: RDX NM_002906.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: -2.20
• Publications: 3 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.37).
• BP6: Variant 11-110264073-C-A is Benign according to our data. Variant chr11-110264073-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165054.
• BP7: Synonymous conserved (PhyloP=-2.2 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.000486 (74/152168) while in subpopulation EAS AF = 0.00848 (44/5188). AF 95% confidence interval is 0.00649. There are 1 homozygotes in GnomAd4. There are 44 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 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.354G>T	p.Pro118Pro	synonymous	Exon 5 of 14	NP_002897.1	B0YJ88
	RDX	NM_001440509.1		c.354G>T	p.Pro118Pro	synonymous	Exon 5 of 15	NP_001427438.1
	RDX	NM_001260492.2		c.354G>T	p.Pro118Pro	synonymous	Exon 5 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.354G>T	p.Pro118Pro	synonymous	Exon 5 of 14	ENSP00000496503.2	P35241-1
	RDX	ENST00000528498.5	TSL:1	c.354G>T	p.Pro118Pro	synonymous	Exon 5 of 16	ENSP00000432112.1	P35241-5
	RDX	ENST00000530301.5	TSL:1	c.258G>T	p.Pro86Pro	synonymous	Exon 4 of 8	ENSP00000436277.1	P35241-3

Frequencies

GnomAD3 genomes AF: 0.000487 AC: 74 AN: 152050 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

Gnomad ASJ AF: 0.00433

Gnomad EAS AF: 0.00846

Gnomad SAS AF: 0.00166

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.00129 AC: 324 AN: 251104 AF XY: 0.00123

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00466

Gnomad EAS exome AF: 0.0142

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.000979

GnomAD4 exome AF: 0.000364 AC: 532 AN: 1461530 Hom.: 5 Cov.: 32 AF XY: 0.000347 AC XY: 252 AN XY: 727080

African (AFR) AF: 0.00 AC: 0 AN: 33470

American (AMR) AF: 0.00 AC: 0 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.00482 AC: 126 AN: 26128

East Asian (EAS) AF: 0.00731 AC: 290 AN: 39694

South Asian (SAS) AF: 0.000510 AC: 44 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5764

European-Non Finnish (NFE) AF: 0.0000171 AC: 19 AN: 1111726

Other (OTH) AF: 0.000861 AC: 52 AN: 60370

GnomAD4 genome AF: 0.000486 AC: 74 AN: 152168 Hom.: 1 Cov.: 32 AF XY: 0.000592 AC XY: 44 AN XY: 74382

African (AFR) AF: 0.00 AC: 0 AN: 41522

American (AMR) AF: 0.0000655 AC: 1 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00433 AC: 15 AN: 3468

East Asian (EAS) AF: 0.00848 AC: 44 AN: 5188

South Asian (SAS) AF: 0.00166 AC: 8 AN: 4816

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68012

Other (OTH) AF: 0.00142 AC: 3 AN: 2108

Alfa AF: 0.000321 Hom.: 0

Bravo AF: 0.000654

Asia WGS AF: 0.00433 AC: 15 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	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	-0.37
CADD	Benign	3.4
DANN	Benign	0.56
PhyloP100		-2.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs144543614; hg19: chr11-110134798;