rs1553637470

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1PM2PP2PP3_ModeratePP5_Moderate

The ENST00000330688.9(RARB):​c.872A>T​(p.His291Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H291P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

RARB
ENST00000330688.9 missense

Scores

8
7
2

Clinical Significance

Likely pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 9.32
Variant links:
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 9 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in ENST00000330688.9
PM2
Very rare variant in population databases, with high coverage;
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.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.897
PP5
Variant 3-25593588-A-T is Pathogenic according to our data. Variant chr3-25593588-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559901.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RARBNM_000965.5 linkuse as main transcriptc.872A>T p.His291Leu missense_variant 6/8 ENST00000330688.9 NP_000956.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RARBENST00000330688.9 linkuse as main transcriptc.872A>T p.His291Leu missense_variant 6/81 NM_000965.5 ENSP00000332296 P1P10826-2

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Likely pathogenic
Submissions summary: Pathogenic:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Microphthalmia, syndromic 12 Pathogenic:1
Likely pathogenic, criteria provided, single submitterclinical testingEquipe Genetique des Anomalies du Developpement, Université de BourgogneAug 16, 2017- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
0.49
D
BayesDel_noAF
Pathogenic
0.46
CADD
Pathogenic
26
DANN
Uncertain
0.98
DEOGEN2
Uncertain
0.69
D;.;.;.
Eigen
Uncertain
0.57
Eigen_PC
Uncertain
0.66
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Uncertain
0.90
D;.;D;D
M_CAP
Pathogenic
0.38
D
MetaRNN
Pathogenic
0.90
D;D;D;D
MetaSVM
Pathogenic
0.89
D
MutationTaster
Benign
1.0
D;D;D;D
PrimateAI
Pathogenic
0.92
D
PROVEAN
Pathogenic
-8.1
D;D;D;D
REVEL
Pathogenic
0.86
Sift
Benign
0.066
T;T;T;T
Sift4G
Uncertain
0.054
T;T;T;T
Vest4
0.81, 0.78
MutPred
0.65
Loss of disorder (P = 0.1208);.;.;.;
MVP
0.99
MPC
2.1
ClinPred
1.0
D
GERP RS
6.0
gMVP
0.87

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: rs1553637470; hg19: chr3-25635079; API