rs1286654

Variant names:

• chr3-25489774-C-A
• rs1286654
• NM_000965.5:c.307-11408C>A

Variant summary

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

The NM_000965.5(RARB):​c.307-11408C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.285 in 152,112 control chromosomes in the GnomAD database, including 6,367 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 0.28 (6367 hom., cov: 34)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0620
• Publications: 6 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.437 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.307-11408C>A		intron_variant	Intron 2 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.307-11408C>A		intron_variant	Intron 2 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.285 AC: 43274 AN: 151994 Hom.: 6357 Cov.: 34

Gnomad AFR AF: 0.255

Gnomad AMI AF: 0.178

Gnomad AMR AF: 0.352

Gnomad ASJ AF: 0.305

Gnomad EAS AF: 0.453

Gnomad SAS AF: 0.268

Gnomad FIN AF: 0.313

Gnomad MID AF: 0.332

Gnomad NFE AF: 0.271

Gnomad OTH AF: 0.303

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

GnomAD4 genome AF: 0.285 AC: 43315 AN: 152112 Hom.: 6367 Cov.: 34 AF XY: 0.288 AC XY: 21419 AN XY: 74354

African (AFR) AF: 0.255 AC: 10594 AN: 41514

American (AMR) AF: 0.352 AC: 5383 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.305 AC: 1058 AN: 3472

East Asian (EAS) AF: 0.453 AC: 2332 AN: 5152

South Asian (SAS) AF: 0.267 AC: 1288 AN: 4826

European-Finnish (FIN) AF: 0.313 AC: 3306 AN: 10552

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.271 AC: 18443 AN: 67994

Other (OTH) AF: 0.308 AC: 650 AN: 2112

Alfa AF: 0.280 Hom.: 10243

Bravo AF: 0.290

Asia WGS AF: 0.367 AC: 1272 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	2.8
DANN	Benign	0.73
PhyloP100		-0.062
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: rs1286654; hg19: chr3-25531265;