rs1387195672
Variant summary
Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2PP2PP3_Strong
The NM_000965.5(RARB):c.410G>A(p.Arg137Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000124 in 1,609,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 6.9e-7 ( 0 hom. )
Consequence
RARB
NM_000965.5 missense
NM_000965.5 missense
Scores
13
3
1
Clinical Significance
Conservation
PhyloP100: 10.0
Genes affected
RARB (HGNC:9865): (retinoic acid receptor beta) This gene encodes retinoic acid receptor beta, a member of the thyroid-steroid hormone receptor superfamily of nuclear transcriptional regulators. This receptor localizes to the cytoplasm and to subnuclear compartments. It binds retinoic acid, the biologically active form of vitamin A which mediates cellular signalling in embryonic morphogenesis, cell growth and differentiation. It is thought that this protein limits growth of many cell types by regulating gene expression. The gene was first identified in a hepatocellular carcinoma where it flanks a hepatitis B virus integration site. Alternate promoter usage and differential splicing result in multiple transcript variants. [provided by RefSeq, Mar 2014]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 7 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
PP2
?
Missense variant where missense usually causes diseases, RARB
PP3
?
MetaRNN computational evidence supports a deleterious effect, 0.988
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RARB | NM_000965.5 | c.410G>A | p.Arg137Gln | missense_variant | 3/8 | ENST00000330688.9 | |
LOC124909356 | XR_007095847.1 | n.902C>T | non_coding_transcript_exon_variant | 2/2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RARB | ENST00000330688.9 | c.410G>A | p.Arg137Gln | missense_variant | 3/8 | 1 | NM_000965.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000659 AC: 1AN: 151752Hom.: 0 Cov.: 32
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GnomAD4 exome AF: 6.86e-7 AC: 1AN: 1457420Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0AN XY: 724912
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Microphthalmia, syndromic 12 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Jan 29, 2024 | This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 137 of the RARB protein (p.Arg137Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of RARB-related disorders (PMID: 31816153). This variant is also known as NM_000965.4:c.410G>A (p.Arg144Gln) . ClinVar contains an entry for this variant (Variation ID: 541542). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt RARB protein function with a positive predictive value of 80%. Experimental studies have shown that this missense change affects RARB function (PMID: 31816153). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Pathogenic
DEOGEN2
Pathogenic
D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D;.;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D
MetaSVM
Pathogenic
D
MutationTaster
Benign
D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Uncertain
D;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;D;D
Sift4G
Uncertain
D;D;D;D
Vest4
0.96
MutPred
Loss of MoRF binding (P = 0.0149);.;.;.;
MVP
MPC
1.3
ClinPred
D
GERP RS
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at