dbSNP rs2234960: RXRA:p.Pro261Leu (chr9-134421677-C-T) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_002957.6(RXRA):c.782C>T(p.Pro261Leu) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00045 in 1,559,812 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

Frequency

Genomes: 𝑓 0.00026 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00047 ( 8 hom. )

Consequence

RXRA
NM_002957.6 missense, splice_region

Scores

Splicing: ADA: 0.01388

Clinical Significance

Not reported in ClinVar

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:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.009608179).

BS2

High AC in GnomAd4 at 40 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXRA	NM_002957.6 link	c.782C>T	p.Pro261Leu	missense_variant, splice_region_variant	Exon 6 of 10	ENST00000481739.2	NP_002948.1	P19793-1F1D8Q5Q6P3U7
RXRA	NM_001291920.2 link	c.701C>T	p.Pro234Leu	missense_variant, splice_region_variant	Exon 6 of 10		NP_001278849.1	A0A5F9ZHH6Q6P3U7
RXRA	NM_001291921.2 link	c.491C>T	p.Pro164Leu	missense_variant, splice_region_variant	Exon 5 of 9		NP_001278850.1	P19793-2Q6P3U7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RXRA	ENST00000481739.2 link	c.782C>T	p.Pro261Leu	missense_variant, splice_region_variant	Exon 6 of 10	1	NM_002957.6	ENSP00000419692.1	P19793-1
RXRA	ENST00000672570.1 link	c.701C>T	p.Pro234Leu	missense_variant, splice_region_variant	Exon 6 of 10			ENSP00000500402.1	A0A5F9ZHH6
RXRA	ENST00000356384.4 link	n.1192C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.000276

AC:

AN:

152110

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000579

Gnomad SAS

AF:

0.00724

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000441

Gnomad OTH

AF:

0.000479

GnomAD3 exomes

AF:

0.000848

AC:

182

AN:

214652

Hom.:

AF XY:

0.00119

AC XY:

135

AN XY:

113448

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000111

Gnomad SAS exome

AF:

0.00791

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000515

Gnomad OTH exome

AF:

0.000386

GnomAD4 exome

AF:

0.000470

AC:

662

AN:

1407584

Hom.:

Cov.:

AF XY:

0.000686

AC XY:

475

AN XY:

692084

show subpopulations

Gnomad4 AFR exome

AF:

0.0000307

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000256

Gnomad4 SAS exome

AF:

0.00742

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000583

Gnomad4 OTH exome

AF:

0.000345

GnomAD4 genome

AF:

0.000263

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74414

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000193

Gnomad4 SAS

AF:

0.00725

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.000474

Alfa

AF:

0.0000634

Hom.:

Bravo

AF:

0.0000491

ExAC

AF:

0.00109

AC:

132

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

DANN

Benign

0.96

DEOGEN2

Benign

0.41

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.094

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.95

MetaRNN

Benign

0.0096

MetaSVM

Benign

-1.0

MutationAssessor

Benign

1.8

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.29

Sift

Benign

0.050

Sift4G

Benign

0.12

Polyphen

0.14

Vest4

0.42

MutPred

0.10

Loss of glycosylation at P261 (P = 0.0125);

MVP

0.89

MPC

1.2

ClinPred

0.17

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.32

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.014

dbscSNV1_RF

Benign

0.11

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over