NM_021976.5:c.864T>G

Variant names:

• chr6-33196563-A-C
• rs1446563333
• NM_021976.5:c.864T>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_021976.5(RXRB):​c.864T>G​(p.Asp288Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000688 in 1,452,864 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.262
• Publications: 0 publications found

Genes affected

RXRB (HGNC:10478): (retinoid X receptor beta) This gene encodes a member of the retinoid X receptor (RXR) family of nuclear receptors which are involved in mediating the effects of retinoic acid (RA). The encoded protein forms homodimers with the retinoic acid, thyroid hormone, and vitamin D receptors, increasing both DNA binding and transcriptional function on their respective response elements. This gene lies within the major histocompatibility complex (MHC) class II region on chromosome 6. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Jul 2012]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.021372259).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_021976.5. 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
	RXRB	NM_021976.5	MANE Select	c.864T>G	p.Asp288Glu	missense	Exon 5 of 10	NP_068811.1	Q5STP9
	RXRB	NM_001270401.2		c.864T>G	p.Asp288Glu	missense	Exon 5 of 10	NP_001257330.1	A0A0S2Z570
	RXRB	NM_001291989.2		c.294T>G	p.Asp98Glu	missense	Exon 4 of 9	NP_001278918.1	A0A0G2JKR7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRB	ENST00000374680.4	TSL:1 MANE Select	c.864T>G	p.Asp288Glu	missense	Exon 5 of 10	ENSP00000363812.3	P28702-1
	RXRB	ENST00000374685.8	TSL:1	c.864T>G	p.Asp288Glu	missense	Exon 5 of 10	ENSP00000363817.4	P28702-3
	RXRB	ENST00000865272.1		c.864T>G	p.Asp288Glu	missense	Exon 5 of 10	ENSP00000535331.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.88e-7 AC: 1 AN: 1452864 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 723108

African (AFR) AF: 0.00 AC: 0 AN: 33340

American (AMR) AF: 0.00 AC: 0 AN: 44652

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26020

East Asian (EAS) AF: 0.00 AC: 0 AN: 39618

South Asian (SAS) AF: 0.00 AC: 0 AN: 86056

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5746

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105388

Other (OTH) AF: 0.00 AC: 0 AN: 60072

GnomAD4 genome Cov.: 32

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	0.066
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.52
CADD	Benign	14
DANN	Benign	0.85
DEOGEN2	Benign	0.27	T
Eigen	Benign	-0.94
Eigen_PC	Benign	-0.75
FATHMM_MKL	Benign	0.27	N
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.021	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	-0.86	N
PhyloP100		-0.26
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	1.2	N
REVEL	Benign	0.15
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.037	B
Vest4		0.061
MutPred		0.24		Gain of ubiquitination at K283 (P = 0.1797)
MVP		0.41
MPC		0.96
ClinPred		0.058	T
GERP RS		2.4
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Varity_R		0.039
gMVP		0.076
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs1446563333; hg19: chr6-33164340;