rs1805348

Variant names:

• chr9-134436596-G-A
• rs1805348
• NM_002957.6:c.1371G>A

Variant summary

Our verdict is Benign. Variant got -11 ACMG points: 0P and 11B. BP4_Moderate BP7 BS1 BS2

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
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -4.16

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]

ACMG classification

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• 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	c.1371G>A	p.Ala457Ala	synonymous_variant	Exon 10 of 10	ENST00000481739.2	NP_002948.1
RXRA	NM_001291920.2	c.1290G>A	p.Ala430Ala	synonymous_variant	Exon 10 of 10		NP_001278849.1
RXRA	NM_001291921.2	c.1080G>A	p.Ala360Ala	synonymous_variant	Exon 9 of 9		NP_001278850.1

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0139 AC: 2111 AN: 152228 Hom.: 28 Cov.: 33

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

GnomAD3 exomes AF: 0.0137 AC: 3437 AN: 251180 Hom.: 48 AF XY: 0.0137 AC XY: 1859 AN XY: 135824

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 SAS exome AF: 0.000294

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.: 33 AF XY: 0.0163 AC XY: 11843 AN XY: 727116

Gnomad4 AFR exome AF: 0.00194

Gnomad4 AMR exome AF: 0.0107

Gnomad4 ASJ exome AF: 0.0254

Gnomad4 EAS exome AF: 0.00229

Gnomad4 SAS exome AF: 0.000313

Gnomad4 FIN exome AF: 0.0334

Gnomad4 NFE exome AF: 0.0182

Gnomad4 OTH exome AF: 0.0133

GnomAD4 genome AF: 0.0139 AC: 2112 AN: 152346 Hom.: 28 Cov.: 33 AF XY: 0.0148 AC XY: 1100 AN XY: 74498

Gnomad4 AFR AF: 0.00334

Gnomad4 AMR AF: 0.0140

Gnomad4 ASJ AF: 0.0314

Gnomad4 EAS AF: 0.00212

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.0436

Gnomad4 NFE AF: 0.0169

Gnomad4 OTH AF: 0.0104

Alfa AF: 0.0165 Hom.: 32

Bravo AF: 0.0116

Asia WGS AF: 0.00115 AC: 4 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
DANN	Benign	0.69

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: rs1805348; hg19: chr9-137328442;