Genetic Variant RXRA:p.Ala457Ala (chr9-134436596-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BS1BS2

The NM_002957.6(RXRA):c.1371G>A(p.Ala457Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0163 in 1,613,970 control chromosomes in the GnomAD database, including 277 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.014 ( 28 hom., cov: 33)

Exomes 𝑓: 0.017 ( 249 hom. )

Consequence

RXRA
NM_002957.6 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -4.16

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:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.41).

BP7

Synonymous conserved (PhyloP=-4.16 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0139 (2112/152346) while in subpopulation NFE AF = 0.0169 (1151/68032). AF 95% confidence interval is 0.0161. There are 28 homozygotes in GnomAd4. There are 1100 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High AC in GnomAd4 at 2112 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXRA	NM_002957.6 link	c.1371G>A	p.Ala457Ala	synonymous_variant	Exon 10 of 10	ENST00000481739.2	NP_002948.1	P19793-1F1D8Q5Q6P3U7
RXRA	NM_001291920.2 link	c.1290G>A	p.Ala430Ala	synonymous_variant	Exon 10 of 10		NP_001278849.1	A0A5F9ZHH6Q6P3U7
RXRA	NM_001291921.2 link	c.1080G>A	p.Ala360Ala	synonymous_variant	Exon 9 of 9		NP_001278850.1	P19793-2Q6P3U7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RXRA	ENST00000481739.2 link	c.1371G>A	p.Ala457Ala	synonymous_variant	Exon 10 of 10	1	NM_002957.6	ENSP00000419692.1	P19793-1
RXRA	ENST00000672570.1 link	c.1290G>A	p.Ala430Ala	synonymous_variant	Exon 10 of 10			ENSP00000500402.1	A0A5F9ZHH6
RXRA	ENST00000356384.4 link	n.1781G>A		non_coding_transcript_exon_variant	Exon 12 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.0139

AC:

2111

AN:

152228

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00333

Gnomad AMI

AF:

0.00219

Gnomad AMR

AF:

0.0141

Gnomad ASJ

AF:

0.0314

Gnomad EAS

AF:

0.00212

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0436

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0169

Gnomad OTH

AF:

0.0105

GnomAD2 exomes

AF:

0.0137

AC:

3437

AN:

251180

AF XY:

0.0137

show subpopulations

Gnomad AFR exome

AF:

0.00246

Gnomad AMR exome

AF:

0.0106

Gnomad ASJ exome

AF:

0.0242

Gnomad EAS exome

AF:

0.00169

Gnomad FIN exome

AF:

0.0369

Gnomad NFE exome

AF:

0.0163

Gnomad OTH exome

AF:

0.0153

GnomAD4 exome

AF:

0.0165

AC:

24121

AN:

1461624

Hom.:

249

Cov.:

AF XY:

0.0163

AC XY:

11843

AN XY:

727116

show subpopulations

African (AFR)

AF:

0.00194

AC:

AN:

33480

American (AMR)

AF:

0.0107

AC:

479

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0254

AC:

663

AN:

26136

East Asian (EAS)

AF:

0.00229

AC:

AN:

39700

South Asian (SAS)

AF:

0.000313

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.0334

AC:

1777

AN:

53196

Middle Eastern (MID)

AF:

0.00312

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0182

AC:

20199

AN:

1111972

Other (OTH)

AF:

0.0133

AC:

802

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

1256

2512

3768

5024

6280

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

798

1596

2394

3192

3990

<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:

0.0139

AC:

2112

AN:

152346

Hom.:

Cov.:

AF XY:

0.0148

AC XY:

1100

AN XY:

74498

show subpopulations

African (AFR)

AF:

0.00334

AC:

139

AN:

41574

American (AMR)

AF:

0.0140

AC:

215

AN:

15310

Ashkenazi Jewish (ASJ)

AF:

0.0314

AC:

109

AN:

3472

East Asian (EAS)

AF:

0.00212

AC:

AN:

5188

South Asian (SAS)

AF:

0.00

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0436

AC:

463

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0169

AC:

1151

AN:

68032

Other (OTH)

AF:

0.0104

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

108

215

323

430

538

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

120

<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:

0.0151

Hom.:

Bravo

AF:

0.0116

Asia WGS

AF:

0.00115

AC:

AN:

3478

EpiCase

AF:

0.0186

EpiControl

AF:

0.0181

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.41

CADD

Benign

4.7

(source)

DANN

Benign

0.69

PhyloP100

-4.2

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over