9-134429149-A-G

Variant summary

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

The NM_002957.6(RXRA):ā€‹c.952A>Gā€‹(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 (ā˜…).

Frequency

Genomes: š‘“ 0.00014 ( 0 hom., cov: 34)
Exomes š‘“: 0.000025 ( 0 hom. )

Consequence

RXRA
NM_002957.6 missense

Scores

8
11

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]

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
RXRANM_002957.6 linkc.952A>G p.Ile318Val missense_variant Exon 7 of 10 ENST00000481739.2 NP_002948.1 P19793-1F1D8Q5Q6P3U7
RXRANM_001291920.2 linkc.871A>G p.Ile291Val missense_variant Exon 7 of 10 NP_001278849.1 A0A5F9ZHH6Q6P3U7
RXRANM_001291921.2 linkc.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 Appris UniProt
RXRAENST00000481739.2 linkc.952A>G p.Ile318Val missense_variant Exon 7 of 10 1 NM_002957.6 ENSP00000419692.1 P19793-1
RXRAENST00000672570.1 linkc.871A>G p.Ile291Val missense_variant Exon 7 of 10 ENSP00000500402.1 A0A5F9ZHH6
RXRAENST00000356384.4 linkn.1362A>G non_coding_transcript_exon_variant Exon 9 of 12 5

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152188
Hom.:
0
Cov.:
34
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:
10
AN:
250816
Hom.:
0
AF XY:
0.0000442
AC XY:
6
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:
37
AN:
1460786
Hom.:
0
Cov.:
33
AF XY:
0.0000261
AC XY:
19
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:
21
AN:
152306
Hom.:
0
Cov.:
34
AF XY:
0.000134
AC XY:
10
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.:
0
Bravo
AF:
0.000162
ESP6500AA
AF:
0.000681
AC:
3
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000659
AC:
8

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
T
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
21
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.51
D
Eigen
Benign
-0.27
Eigen_PC
Benign
-0.091
FATHMM_MKL
Benign
0.75
D
LIST_S2
Uncertain
0.93
D
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.13
T
MetaSVM
Uncertain
0.29
D
MutationAssessor
Benign
0.55
N
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-0.28
N
REVEL
Uncertain
0.36
Sift
Benign
0.37
T
Sift4G
Benign
0.43
T
Polyphen
0.0070
B
Vest4
0.17
MVP
0.75
MPC
2.0
ClinPred
0.044
T
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.

Other links and lift over

dbSNP: rs143509964; hg19: chr9-137320995; API