chr9-134436600-C-T

Variant names:

• chr9-134436600-C-T
• NM_002957.6:c.1375C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP2

The NM_002957.6(RXRA):​c.1375C>T​(p.His459Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RXRA NM_002957.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.62
• Publications: 0 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 3 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.9681 (below the threshold of 3.09). Trascript score misZ: 3.5958 (above the threshold of 3.09).

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.1375C>T	p.His459Tyr	missense	Exon 10 of 10	NP_002948.1	P19793-1
	RXRA	NM_001291920.2		c.1294C>T	p.His432Tyr	missense	Exon 10 of 10	NP_001278849.1	A0A5F9ZHH6
	RXRA	NM_001291921.2		c.1084C>T	p.His362Tyr	missense	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.1375C>T	p.His459Tyr	missense	Exon 10 of 10	ENSP00000419692.1	P19793-1
	RXRA	ENST00000672570.1		c.1294C>T	p.His432Tyr	missense	Exon 10 of 10	ENSP00000500402.1	A0A5F9ZHH6
	RXRA	ENST00000356384.4	TSL:5	n.1785C>T		non_coding_transcript_exon	Exon 12 of 12

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.22
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Uncertain	0.58	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Benign	0.63	N
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.64
Sift	Benign	0.033	D
Sift4G	Benign	0.19	T
Polyphen		0.90	P
Vest4		0.44
MutPred		0.41		Loss of solvent accessibility (P = 0.0238)
MVP		0.83
MPC		2.4
ClinPred		0.87	D
GERP RS		4.8
Varity_R		0.58
gMVP		0.60
Mutation Taster		=27/73	disease causing

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

hg19: chr9-137328446;