rs1286763

Variant names:

• chr3-25557045-G-T
• rs1286763
• NM_000965.5:c.449-12713G>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000965.5(RARB):​c.449-12713G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.631 in 151,956 control chromosomes in the GnomAD database, including 32,364 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.63 (32364 hom., cov: 31)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.670
• Publications: 5 publications found

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]

RARB Gene-Disease associations (from GenCC):

• microphthalmia, syndromic 12

  Inheritance: AR, AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Baylor College of Medicine Research Center
• Matthew-Wood syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-1.01).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.877 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.449-12713G>T		intron_variant	Intron 3 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.449-12713G>T		intron_variant	Intron 3 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.630 AC: 95722 AN: 151836 Hom.: 32295 Cov.: 31

Gnomad AFR AF: 0.885

Gnomad AMI AF: 0.470

Gnomad AMR AF: 0.670

Gnomad ASJ AF: 0.493

Gnomad EAS AF: 0.585

Gnomad SAS AF: 0.370

Gnomad FIN AF: 0.530

Gnomad MID AF: 0.430

Gnomad NFE AF: 0.516

Gnomad OTH AF: 0.565

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.631 AC: 95857 AN: 151956 Hom.: 32364 Cov.: 31 AF XY: 0.626 AC XY: 46502 AN XY: 74238

African (AFR) AF: 0.885 AC: 36712 AN: 41484

American (AMR) AF: 0.670 AC: 10229 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.493 AC: 1711 AN: 3470

East Asian (EAS) AF: 0.585 AC: 3008 AN: 5144

South Asian (SAS) AF: 0.370 AC: 1782 AN: 4820

European-Finnish (FIN) AF: 0.530 AC: 5586 AN: 10530

Middle Eastern (MID) AF: 0.449 AC: 132 AN: 294

European-Non Finnish (NFE) AF: 0.516 AC: 35070 AN: 67924

Other (OTH) AF: 0.568 AC: 1199 AN: 2110

Alfa AF: 0.571 Hom.: 10714

Bravo AF: 0.657

Asia WGS AF: 0.517 AC: 1801 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-1.0
CADD	Benign	0.35
DANN	Benign	0.48
PhyloP100		-0.67
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1286763; hg19: chr3-25598536;