chr9-134421677-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 1P and 8B. PP2BP4_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. 14/23 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.

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

Publications

8 publications found

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 was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.9681 (below the threshold of 3.09). Trascript score misZ: 3.5958 (above the threshold of 3.09).

BP4

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

BS2

High AC in GnomAd4 at 40 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002957.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RXRA	NM_002957.6	MANE Select	c.782C>T	p.Pro261Leu	missense splice_region	Exon 6 of 10	NP_002948.1
RXRA	NM_001291920.2		c.701C>T	p.Pro234Leu	missense splice_region	Exon 6 of 10	NP_001278849.1
RXRA	NM_001291921.2		c.491C>T	p.Pro164Leu	missense splice_region	Exon 5 of 9	NP_001278850.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
RXRA	ENST00000481739.2	TSL:1 MANE Select	c.782C>T	p.Pro261Leu	missense splice_region	Exon 6 of 10	ENSP00000419692.1
RXRA	ENST00000672570.1		c.701C>T	p.Pro234Leu	missense splice_region	Exon 6 of 10	ENSP00000500402.1
RXRA	ENST00000356384.4	TSL:5	n.1192C>T		splice_region non_coding_transcript_exon	Exon 8 of 12

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

GnomAD2 exomes

AF:

0.000848

AC:

182

AN:

214652

AF XY:

0.00119

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 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

African (AFR)

AF:

0.0000307

AC:

AN:

32622

American (AMR)

AF:

0.00

AC:

AN:

41236

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22488

East Asian (EAS)

AF:

0.0000256

AC:

AN:

39078

South Asian (SAS)

AF:

0.00742

AC:

575

AN:

77536

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51144

Middle Eastern (MID)

AF:

0.000364

AC:

AN:

5498

European-Non Finnish (NFE)

AF:

0.0000583

AC:

AN:

1079938

Other (OTH)

AF:

0.000345

AC:

AN:

58044

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.474

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000263

AC:

AN:

152228

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74414

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41522

American (AMR)

AF:

0.00

AC:

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.00725

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10620

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68000

Other (OTH)

AF:

0.000474

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000516

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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.090

CADD

Uncertain

(source)

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

PhyloP100

7.5

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

Mutation Taster

=15/85

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over