9-134409080-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong

The NM_002957.6(RXRA):c.571C>T(p.Arg191Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000344 in 1,454,362 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 13/21 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 34)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

RXRA
NM_002957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.55

Variant links:

Genes affected

RXRA (HGNC:10477): (retinoid X receptor alpha) Retinoid X receptors (RXRs) and retinoic acid receptors (RARs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. These receptors function as transcription factors by binding as homodimers or heterodimers to specific sequences in the promoters of target genes. The protein encoded by this gene is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

RXRA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP2

Missense variant where missense usually causes diseases, RXRA

PP3

MetaRNN computational evidence supports a deleterious effect, 0.981

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
RXRA	NM_002957.6 linkuse as main transcript	c.571C>T	p.Arg191Cys	missense_variant	4/10	ENST00000481739.2
RXRA	NM_001291920.2 linkuse as main transcript	c.490C>T	p.Arg164Cys	missense_variant	4/10
RXRA	NM_001291921.2 linkuse as main transcript	c.280C>T	p.Arg94Cys	missense_variant	3/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRA	ENST00000481739.2 linkuse as main transcript	c.571C>T	p.Arg191Cys	missense_variant	4/10	1	NM_002957.6	P3	P19793-1
RXRA	ENST00000672570.1 linkuse as main transcript	c.490C>T	p.Arg164Cys	missense_variant	4/10			A1
RXRA	ENST00000356384.4 linkuse as main transcript	n.981C>T		non_coding_transcript_exon_variant	6/12	5

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000410

AC:

AN:

243724

Hom.:

AF XY:

0.00

AC XY:

AN XY:

132170

show subpopulations

Gnomad AFR exome

AF:

0.0000628

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000344

AC:

AN:

1454362

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

723446

show subpopulations

Gnomad4 AFR exome

AF:

0.0000302

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:

0.00000271

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 25, 2023

The c.571C>T (p.R191C) alteration is located in exon 4 (coding exon 4) of the RXRA gene. This alteration results from a C to T substitution at nucleotide position 571, causing the arginine (R) at amino acid position 191 to be replaced by a cysteine (C). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.56

BayesDel_noAF

Pathogenic

0.56

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.80

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.84

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.92

M_CAP

Pathogenic

0.91

MetaRNN

Pathogenic

0.98

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

4.9

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.92

PROVEAN

Pathogenic

-6.7

REVEL

Pathogenic

0.95

Sift

Uncertain

0.0030

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.97

MutPred

0.85

Loss of MoRF binding (P = 0.0067);

MVP

0.98

MPC

2.6

ClinPred

1.0

GERP RS

4.5

Varity_R

0.93

gMVP

0.99

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over