chr3-25174432-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001290216.3(RARB):​c.35C>T​(p.Ala12Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000303 in 1,352,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 9/13 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (no stars).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000033 ( 0 hom. )

Consequence

RARB
NM_001290216.3 missense

Scores

1
3
12

Clinical Significance

Uncertain significance no assertion criteria provided U:1

Conservation

PhyloP100: 5.75
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.24125892).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
RARBNM_001290216.3 linkuse as main transcriptc.35C>T p.Ala12Val missense_variant 4/11 NP_001277145.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
RARBENST00000383772.9 linkuse as main transcriptc.35C>T p.Ala12Val missense_variant 5/125 ENSP00000373282 P10826-1
RARBENST00000686715.1 linkuse as main transcriptc.35C>T p.Ala12Val missense_variant 5/12 ENSP00000510539 P10826-1
RARBENST00000687353.1 linkuse as main transcriptc.35C>T p.Ala12Val missense_variant 6/13 ENSP00000508588 P10826-1

Frequencies

GnomAD3 genomes
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000742
AC:
17
AN:
229250
Hom.:
0
AF XY:
0.0000789
AC XY:
10
AN XY:
126668
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.0000858
Gnomad NFE exome
AF:
0.000142
Gnomad OTH exome
AF:
0.000171
GnomAD4 exome
AF:
0.0000333
AC:
40
AN:
1199838
Hom.:
0
Cov.:
30
AF XY:
0.0000370
AC XY:
22
AN XY:
594988
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.0000581
Gnomad4 NFE exome
AF:
0.0000367
Gnomad4 OTH exome
AF:
0.0000911
GnomAD4 genome
AF:
0.00000657
AC:
1
AN:
152204
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74356
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000712
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.000121
AC:
14
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: no assertion criteria provided
LINK: link

Submissions by phenotype

RARB-related disorder Uncertain:1
Uncertain significance, no assertion criteria providedclinical testingPreventionGenetics, part of Exact SciencesJan 05, 2024The RARB c.35C>T variant is predicted to result in the amino acid substitution p.Ala12Val. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.014% of alleles in individuals of European (Non-Finnish) descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Benign
-0.13
T
BayesDel_noAF
Benign
-0.17
CADD
Benign
23
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.067
T
Eigen
Benign
-0.040
Eigen_PC
Benign
0.088
FATHMM_MKL
Benign
0.69
D
LIST_S2
Benign
0.52
T
M_CAP
Benign
0.058
D
MetaRNN
Benign
0.24
T
MetaSVM
Uncertain
0.14
D
MutationTaster
Benign
0.71
N
PROVEAN
Benign
-0.58
N
REVEL
Uncertain
0.37
Sift
Uncertain
0.015
D
Sift4G
Benign
0.57
T
MutPred
0.67
Loss of disorder (P = 0.0786);
MVP
0.70
ClinPred
0.17
T
GERP RS
5.9

Splicing

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: rs774685508; hg19: chr3-25215923; API