9-134429009-G-T

Variant names:

• chr9-134429009-G-T
• rs3118570
• NM_002957.6:c.911-99G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_002957.6(RXRA):​c.911-99G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.822 in 1,460,516 control chromosomes in the GnomAD database, including 495,853 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 0.86 (56440 hom., cov: 34)
  • Exomes 𝑓: 0.82 (439413 hom.)
• Consequence: RXRA NM_002957.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -3.55
• Publications: 20 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.956 is higher than 0.05.

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.911-99G>T		intron	N/A	NP_002948.1	P19793-1
	RXRA	NM_001291920.2		c.830-99G>T		intron	N/A	NP_001278849.1	A0A5F9ZHH6
	RXRA	NM_001291921.2		c.620-99G>T		intron	N/A	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.911-99G>T		intron	N/A	ENSP00000419692.1	P19793-1
	RXRA	ENST00000672570.1		c.830-99G>T		intron	N/A	ENSP00000500402.1	A0A5F9ZHH6
	RXRA	ENST00000356384.4	TSL:5	n.1321-99G>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.858 AC: 130502 AN: 152138 Hom.: 56386 Cov.: 34

Gnomad AFR AF: 0.963

Gnomad AMI AF: 0.909

Gnomad AMR AF: 0.812

Gnomad ASJ AF: 0.775

Gnomad EAS AF: 0.809

Gnomad SAS AF: 0.688

Gnomad FIN AF: 0.857

Gnomad MID AF: 0.693

Gnomad NFE AF: 0.825

Gnomad OTH AF: 0.826

GnomAD4 exome AF: 0.818 AC: 1070498 AN: 1308260 Hom.: 439413 AF XY: 0.813 AC XY: 528335 AN XY: 649980

African (AFR) AF: 0.968 AC: 29314 AN: 30278

American (AMR) AF: 0.761 AC: 28777 AN: 37808

Ashkenazi Jewish (ASJ) AF: 0.797 AC: 17247 AN: 21638

East Asian (EAS) AF: 0.781 AC: 30169 AN: 38642

South Asian (SAS) AF: 0.672 AC: 50776 AN: 75514

European-Finnish (FIN) AF: 0.850 AC: 39140 AN: 46068

Middle Eastern (MID) AF: 0.733 AC: 3763 AN: 5134

European-Non Finnish (NFE) AF: 0.828 AC: 826766 AN: 998516

Other (OTH) AF: 0.815 AC: 44546 AN: 54662

GnomAD4 genome AF: 0.858 AC: 130611 AN: 152256 Hom.: 56440 Cov.: 34 AF XY: 0.856 AC XY: 63721 AN XY: 74424

African (AFR) AF: 0.963 AC: 40047 AN: 41568

American (AMR) AF: 0.812 AC: 12423 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.775 AC: 2690 AN: 3472

East Asian (EAS) AF: 0.809 AC: 4163 AN: 5148

South Asian (SAS) AF: 0.686 AC: 3310 AN: 4822

European-Finnish (FIN) AF: 0.857 AC: 9101 AN: 10622

Middle Eastern (MID) AF: 0.704 AC: 207 AN: 294

European-Non Finnish (NFE) AF: 0.825 AC: 56103 AN: 68000

Other (OTH) AF: 0.822 AC: 1738 AN: 2114

Alfa AF: 0.822 Hom.: 2952

Bravo AF: 0.859

Asia WGS AF: 0.754 AC: 2623 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.24
DANN	Benign	0.65
PhyloP100		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs3118570; hg19: chr9-137320855; COSMIC: COSV62683906;