6-33196472-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PP2 BP4_Strong BP6_Moderate BS2

The NM_021976.5(RXRB):c.955G>A(p.Val319Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000146 in 1,613,080 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00014 (0 hom.)
• Consequence: RXRB NM_021976.5 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.537

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 Benign. Variant got -9 ACMG points.

• PP2: Missense variant where missense usually causes diseases, RXRB
• BP4: Computational evidence support a benign effect (MetaRNN=0.023199797).
• BP6: Variant 6-33196472-C-T is Benign according to our data. Variant chr6-33196472-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2522153.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd at 30 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RXRB	NM_021976.5	c.955G>A	p.Val319Ile	missense_variant	5/10	ENST00000374680.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RXRB	ENST00000374680.4	c.955G>A	p.Val319Ile	missense_variant	5/10	1	NM_021976.5	P4
RXRB	ENST00000374685.8	c.955G>A	p.Val319Ile	missense_variant	5/10	1		A1
RXRB	ENST00000481441.1	n.643G>A		non_coding_transcript_exon_variant	3/3	2
RXRB	ENST00000483281.5	c.*467G>A		3_prime_UTR_variant, NMD_transcript_variant	4/9	5

Frequencies

GnomAD3 genomes AF: 0.000197 AC: 30 AN: 152220 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00105

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000239 AC: 59 AN: 246464 Hom.: 0 AF XY: 0.000231 AC XY: 31 AN XY: 134376

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000551

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000547

Gnomad SAS exome AF: 0.000296

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000262

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000141 AC: 206 AN: 1460742 Hom.: 0 Cov.: 32 AF XY: 0.000144 AC XY: 105 AN XY: 726684

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000604

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000101

Gnomad4 OTH exome AF: 0.000331

GnomAD4 genome AF: 0.000197 AC: 30 AN: 152338 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74484

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.00105

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000186 Hom.: 0

Bravo AF: 0.000162

ExAC AF: 0.000213 AC: 25

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000218

EpiControl AF: 0.000415

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 21, 2023

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.42	T
BayesDel_noAF	Benign	-0.49
Cadd	Benign	18
Dann	Uncertain	0.99
Eigen	Benign	-0.33
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.023	T;T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.28	N;N
MutationTaster	Benign	0.74	D;N;N;N
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.34	N;N
REVEL	Benign	0.11
Sift	Benign	0.38	T;T
Sift4G	Benign	0.55	T;T
Polyphen		0.059	.;B
Vest4		0.087
MVP		0.38
MPC		0.83
ClinPred		0.013	T
GERP RS		4.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.027
gMVP		0.062

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

LitVar

Other links and lift over

dbSNP: rs201059237; hg19: chr6-33164249;