Genetic Variant RXRA:p.Ile318Val (chr9-134429149-A-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_002957.6(RXRA):c.952A>G(p.Ile318Val) variant causes a missense change. The variant allele was found at a frequency of 0.000036 in 1,613,092 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 (★).

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 34)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

RXRA
NM_002957.6 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.16

Variant links:

Genes affected

RXRA (HGNC:10477): (retinoid X receptor alpha) Retinoid X receptors (RXRs) and retinoic acid receptors (RARs) are nuclear receptors that mediate the biological effects of retinoids by their involvement in retinoic acid-mediated gene activation. These receptors function as transcription factors by binding as homodimers or heterodimers to specific sequences in the promoters of target genes. The protein encoded by this gene is a member of the steroid and thyroid hormone receptor superfamily of transcriptional regulators. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2014]

RXRA links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.13010186).

BS2

High AC in GnomAd4 at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RXRA	NM_002957.6 link	c.952A>G	p.Ile318Val	missense_variant	Exon 7 of 10	ENST00000481739.2	NP_002948.1	P19793-1F1D8Q5Q6P3U7
RXRA	NM_001291920.2 link	c.871A>G	p.Ile291Val	missense_variant	Exon 7 of 10		NP_001278849.1	A0A5F9ZHH6Q6P3U7
RXRA	NM_001291921.2 link	c.661A>G	p.Ile221Val	missense_variant	Exon 6 of 9		NP_001278850.1	P19793-2Q6P3U7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
RXRA	ENST00000481739.2 link	c.952A>G	p.Ile318Val	missense_variant	Exon 7 of 10	1	NM_002957.6	ENSP00000419692.1	P19793-1
RXRA	ENST00000672570.1 link	c.871A>G	p.Ile291Val	missense_variant	Exon 7 of 10			ENSP00000500402.1	A0A5F9ZHH6
RXRA	ENST00000356384.4 link	n.1362A>G		non_coding_transcript_exon_variant	Exon 9 of 12	5

Frequencies

GnomAD3 genomes

AF:

0.000138

AC:

AN:

152188

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000458

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000654

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000399

AC:

AN:

250816

Hom.:

AF XY:

0.0000442

AC XY:

AN XY:

135800

show subpopulations

Gnomad AFR exome

AF:

0.000432

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000883

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000253

AC:

AN:

1460786

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

726728

show subpopulations

Gnomad4 AFR exome

AF:

0.000657

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000464

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000809

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.000138

AC:

AN:

152306

Hom.:

Cov.:

AF XY:

0.000134

AC XY:

AN XY:

74482

show subpopulations

Gnomad4 AFR

AF:

0.000457

Gnomad4 AMR

AF:

0.0000654

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000441

Hom.:

Bravo

AF:

0.000162

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 30, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.952A>G (p.I318V) alteration is located in exon 7 (coding exon 7) of the RXRA gene. This alteration results from a A to G substitution at nucleotide position 952, causing the isoleucine (I) at amino acid position 318 to be replaced by a valine (V). 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

0.070

BayesDel_addAF

Benign

-0.067

BayesDel_noAF

Uncertain

-0.020

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.091

FATHMM_MKL

Benign

0.75

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.13

MetaSVM

Uncertain

0.29

MutationAssessor

Benign

0.55

PrimateAI

Uncertain

0.68

PROVEAN

Benign

-0.28

REVEL

Uncertain

0.36

Sift

Benign

0.37

Sift4G

Benign

0.43

Polyphen

0.0070

Vest4

0.17

MVP

0.75

MPC

2.0

ClinPred

0.044

GERP RS

4.3

Varity_R

0.29

gMVP

0.61

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over