6-33199270-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_021976.5(RXRB):c.382C>A(p.Pro128Thr) variant causes a missense change. The variant allele was found at a frequency of 0.0000011 in 911,980 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P128A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.96

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

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, RXRB
• BP4: Computational evidence support a benign effect (MetaRNN=0.13143).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXRB	NM_021976.5	c.382C>A	p.Pro128Thr	missense_variant	2/10	ENST00000374680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRB	ENST00000374680.4	c.382C>A	p.Pro128Thr	missense_variant	2/10	1	NM_021976.5	P4
RXRB	ENST00000374685.8	c.382C>A	p.Pro128Thr	missense_variant	2/10	1		A1
RXRB	ENST00000483281.5	c.236-806C>A		intron_variant, NMD_transcript_variant		5

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 0.00000110 AC: 1 AN: 911980 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 435038

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: 0.00

Gnomad4 OTH exome AF: 0.0000265

GnomAD4 genome Cov.: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3476

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 07, 2023

The c.382C>A (p.P128T) alteration is located in exon 2 (coding exon 2) of the RXRB gene. This alteration results from a C to A substitution at nucleotide position 382, causing the proline (P) at amino acid position 128 to be replaced by a threonine (T). 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	0.068
BayesDel_addAF	Uncertain	0.046	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Benign	0.84
Eigen	Benign	-0.57
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.56	D
M_CAP	Uncertain	0.22	D
MetaRNN	Benign	0.13	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	0.90	L;L
MutationTaster	Benign	0.97	D;D;D;D
PrimateAI	Uncertain	0.75	T
PROVEAN	Benign	0.65	N;N
REVEL	Uncertain	0.33
Sift	Benign	0.44	T;T
Sift4G	Benign	0.16	T;T
Polyphen		0.12	.;B
Vest4		0.38
MutPred		0.30		Gain of phosphorylation at P128 (P = 0.0083);Gain of phosphorylation at P128 (P = 0.0083);
MVP		0.46
MPC		0.51
ClinPred		0.54	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.23
gMVP		0.12

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs371739737; hg19: chr6-33167047;