chr3-25428879-A-G
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Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 1P and 2B. PP2BP4_Moderate
The NM_000965.5(RARB):āc.148A>Gā(p.Thr50Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,611,426 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.000013 ( 0 hom., cov: 33)
Exomes š: 0.0000041 ( 0 hom. )
Consequence
RARB
NM_000965.5 missense
NM_000965.5 missense
Scores
4
12
Clinical Significance
Conservation
PhyloP100: 6.75
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_benign. Variant got -1 ACMG points.
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RARB. . Gene score misZ 2.8661 (greater than the threshold 3.09). Trascript score misZ 3.1257 (greater than threshold 3.09). GenCC has associacion of gene with microphthalmia, syndromic 12, Matthew-Wood syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.16965556).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
RARB | NM_000965.5 | c.148A>G | p.Thr50Ala | missense_variant | 1/8 | ENST00000330688.9 | NP_000956.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
RARB | ENST00000330688.9 | c.148A>G | p.Thr50Ala | missense_variant | 1/8 | 1 | NM_000965.5 | ENSP00000332296 | P1 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 33
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GnomAD4 exome AF: 0.00000411 AC: 6AN: 1459294Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 725466
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152132Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1AN XY: 74316
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Oct 16, 2023 | The c.148A>G (p.T50A) alteration is located in exon 1 (coding exon 1) of the RARB gene. This alteration results from a A to G substitution at nucleotide position 148, causing the threonine (T) at amino acid position 50 to be replaced by an alanine (A). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | GeneDx | Dec 20, 2016 | The T50A variant in the RARB gene has not been reported previously as a pathogenic variant, nor as a benign variant, to our knowledge. The T50A variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The T50A variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is conserved in mammals. In silico analysis is inconsistent in its predictions as to whether or not the variant is damaging to the protein structure/function. We interpret T50A as a variant of uncertain significance. - |
Computational scores
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Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Benign
T
MetaSVM
Uncertain
T
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Benign
N
REVEL
Benign
Sift
Benign
T
Sift4G
Benign
T
Vest4
MutPred
Loss of sheet (P = 0.0457);
MVP
MPC
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