NM_021976.5:c.874G>C

Variant names:

• chr6-33196553-C-G
• rs776600395
• NM_021976.5:c.874G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_021976.5(RXRB):​c.874G>C​(p.Ala292Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000031 in 1,612,432 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict 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. A292T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.53
• 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15552181).

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.874G>C	p.Ala292Pro	missense	Exon 5 of 10	NP_068811.1	Q5STP9
	RXRB	NM_001270401.2		c.874G>C	p.Ala292Pro	missense	Exon 5 of 10	NP_001257330.1	A0A0S2Z570
	RXRB	NM_001291989.2		c.304G>C	p.Ala102Pro	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.874G>C	p.Ala292Pro	missense	Exon 5 of 10	ENSP00000363812.3	P28702-1
	RXRB	ENST00000374685.8	TSL:1	c.874G>C	p.Ala292Pro	missense	Exon 5 of 10	ENSP00000363817.4	P28702-3
	RXRB	ENST00000865272.1		c.874G>C	p.Ala292Pro	missense	Exon 5 of 10	ENSP00000535331.1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000122 AC: 3 AN: 245338 AF XY: 0.00000746

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000871

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1460210 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726442

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000447 AC: 2 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86230

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52284

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111580

Other (OTH) AF: 0.00 AC: 0 AN: 60364

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152222 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

African (AFR) AF: 0.00 AC: 0 AN: 41460

American (AMR) AF: 0.000196 AC: 3 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2088

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000171 AC: 2

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	0.071
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	20
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	T
Eigen	Benign	0.031
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.83	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.16	T
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	0.81	L
PhyloP100		1.5
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.3	N
REVEL	Benign	0.26
Sift	Benign	0.21	T
Sift4G	Benign	0.23	T
Polyphen		0.86	P
Vest4		0.14
MutPred		0.25		Loss of catalytic residue at A292 (P = 0.0559)
MVP		0.60
MPC		1.5
ClinPred		0.36	T
GERP RS		5.0
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.8
Varity_R		0.079
gMVP		0.29
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs776600395; hg19: chr6-33164330;