rs727503393

Positions:

• chr11-110236102-G-T

Variant summary

Our verdict is Likely benign. Variant got -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. 14/21 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

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]

ACMG classification

Verdict is Likely_benign. Variant got -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 id is 165052.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-110236102-G-T is described in Lovd as [Likely_benign].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RDX	NM_002906.4	c.1341C>A	p.His447Gln	missense_variant	12/14	ENST00000645495.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RDX	ENST00000645495.2	c.1341C>A	p.His447Gln	missense_variant	12/14		NM_002906.4	P1

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

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000181

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 17, 2014

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
MutationTaster	Benign	1.0	D;D;D;D;D;D
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

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: rs727503393; hg19: chr11-110106827;