6-33195674-G-T

Variant names:

• chr6-33195674-G-T
• rs6531
• NM_021976.5:c.1152C>A

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_021976.5(RXRB):​c.1152C>A​(p.Phe384Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F384F) has been classified as Benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.99
• Publications: 52 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.877

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRB	NM_021976.5	MANE Select	c.1152C>A	p.Phe384Leu	missense	Exon 7 of 10	NP_068811.1
	RXRB	NM_001270401.2		c.1152C>A	p.Phe384Leu	missense	Exon 7 of 10	NP_001257330.1
	RXRB	NM_001291989.2		c.582C>A	p.Phe194Leu	missense	Exon 6 of 9	NP_001278918.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RXRB	ENST00000374680.4	TSL:1 MANE Select	c.1152C>A	p.Phe384Leu	missense	Exon 7 of 10	ENSP00000363812.3
	RXRB	ENST00000374685.8	TSL:1	c.1152C>A	p.Phe384Leu	missense	Exon 7 of 10	ENSP00000363817.4
	RXRB	ENST00000483281.5	TSL:5	n.*664C>A		non_coding_transcript_exon	Exon 6 of 9	ENSP00000431369.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 56

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.89	D
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.26
FATHMM_MKL	Benign	0.71	D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Benign	-0.67	T
MutationAssessor	Benign	0.98	L
PhyloP100		3.0
PrimateAI	Pathogenic	0.90	D
PROVEAN	Pathogenic	-5.6	D
REVEL	Uncertain	0.49
Sift	Benign	0.043	D
Sift4G	Benign	0.19	T
Polyphen		1.0	D
Vest4		0.84
MutPred		0.49		Loss of helix (P = 0.1299)
MVP		0.85
MPC		1.6
ClinPred		0.94	D
GERP RS		2.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.91
Mutation Taster		=34/66	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

dbSNP: rs6531; hg19: chr6-33163451;