rs1805348

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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
• Publications: 8 publications found

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 Gene-Disease associations (from GenCC):

• congenital heart disease

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

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 Homozygotes in GnomAd4 at 28 Unknown 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRA	NM_002957.6	MANE Select	c.1371G>A	p.Ala457Ala	synonymous	Exon 10 of 10	NP_002948.1	P19793-1
	RXRA	NM_001291920.2		c.1290G>A	p.Ala430Ala	synonymous	Exon 10 of 10	NP_001278849.1	A0A5F9ZHH6
	RXRA	NM_001291921.2		c.1080G>A	p.Ala360Ala	synonymous	Exon 9 of 9	NP_001278850.1	P19793-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRA	ENST00000481739.2	TSL:1 MANE Select	c.1371G>A	p.Ala457Ala	synonymous	Exon 10 of 10	ENSP00000419692.1	P19793-1
	RXRA	ENST00000672570.1		c.1290G>A	p.Ala430Ala	synonymous	Exon 10 of 10	ENSP00000500402.1	A0A5F9ZHH6
	RXRA	ENST00000356384.4	TSL:5	n.1781G>A		non_coding_transcript_exon	Exon 12 of 12

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

GnomAD2 exomes AF: 0.0137 AC: 3437 AN: 251180 AF XY: 0.0137

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

African (AFR) AF: 0.00194 AC: 65 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: 91 AN: 39700

South Asian (SAS) AF: 0.000313 AC: 27 AN: 86258

European-Finnish (FIN) AF: 0.0334 AC: 1777 AN: 53196

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.0182 AC: 20199 AN: 1111972

Other (OTH) AF: 0.0133 AC: 802 AN: 60390

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

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: 11 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.0436 AC: 463 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0169 AC: 1151 AN: 68032

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0151 Hom.: 53

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 v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	4.7
DANN	Benign	0.69
PhyloP100		-4.2
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1805348; hg19: chr9-137328442;