9-134417311-G-C

Variant names:

• chr9-134417311-G-C
• rs986185258
• NM_002957.6:c.764G>C

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_002957.6(RXRA):​c.764G>C​(p.Gly255Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0000185 in 1,461,376 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: RXRA NM_002957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.76

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.21501398).
• BS2: High AC in GnomAdExome4 at 27 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXRA	NM_002957.6	c.764G>C	p.Gly255Ala	missense_variant	Exon 5 of 10	ENST00000481739.2	NP_002948.1
RXRA	NM_001291920.2	c.683G>C	p.Gly228Ala	missense_variant	Exon 5 of 10		NP_001278849.1
RXRA	NM_001291921.2	c.473G>C	p.Gly158Ala	missense_variant	Exon 4 of 9		NP_001278850.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXRA	ENST00000481739.2	c.764G>C	p.Gly255Ala	missense_variant	Exon 5 of 10	1	NM_002957.6	ENSP00000419692.1
RXRA	ENST00000672570.1	c.683G>C	p.Gly228Ala	missense_variant	Exon 5 of 10			ENSP00000500402.1
RXRA	ENST00000356384.4	n.1174G>C		non_coding_transcript_exon_variant	Exon 7 of 12	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461376 Hom.: 0 Cov.: 32 AF XY: 0.0000193 AC XY: 14 AN XY: 727016

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000234

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.764G>C (p.G255A) alteration is located in exon 5 (coding exon 5) of the RXRA gene. This alteration results from a G to C substitution at nucleotide position 764, causing the glycine (G) at amino acid position 255 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.49
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.90	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.84	N
REVEL	Benign	0.069
Sift	Benign	0.17	T
Sift4G	Benign	0.15	T
Polyphen		0.0010	B
Vest4		0.28
MutPred		0.26		Gain of relative solvent accessibility (P = 0.0999);
MVP		0.42
MPC		1.1
ClinPred		0.50	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.38
gMVP		0.59

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: rs986185258; hg19: chr9-137309157;