NM_021976.5:c.503T>A

Variant names:

• chr6-33198445-A-T
• NM_021976.5:c.503T>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021976.5(RXRB):​c.503T>A​(p.Leu168His) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25992042).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXRB	NM_021976.5	c.503T>A	p.Leu168His	missense_variant	Exon 3 of 10	ENST00000374680.4	NP_068811.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RXRB	ENST00000374680.4	c.503T>A	p.Leu168His	missense_variant	Exon 3 of 10	1	NM_021976.5	ENSP00000363812.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.503T>A (p.L168H) alteration is located in exon 3 (coding exon 3) of the RXRB gene. This alteration results from a T to A substitution at nucleotide position 503, causing the leucine (L) at amino acid position 168 to be replaced by a histidine (H). 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	0.19
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	26
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.48	.;T
Eigen	Uncertain	0.29
Eigen_PC	Uncertain	0.36
FATHMM_MKL	Uncertain	0.93	D
M_CAP	Uncertain	0.11	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Uncertain	-0.0095	T
MutationAssessor	Benign	1.0	L;L
PrimateAI	Uncertain	0.79	T
PROVEAN	Benign	-1.0	N;N
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	D;D
Sift4G	Benign	0.38	T;T
Polyphen		0.99	.;D
Vest4		0.20
MutPred		0.25		Loss of sheet (P = 0.0228);Loss of sheet (P = 0.0228);
MVP		0.63
MPC		1.5
ClinPred		0.74	D
GERP RS		5.1
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.38
gMVP		0.098

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr6-33166222;