rs1730240

Variant names:

• chr3-25566022-A-C
• rs1730240
• NM_000965.5:c.449-3736A>C

Variant summary

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

The NM_000965.5(RARB):​c.449-3736A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.46 in 151,890 control chromosomes in the GnomAD database, including 16,238 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 0.46 (16238 hom., cov: 31)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.71
• Publications: 3 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.529 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.449-3736A>C		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.449-3736A>C		intron_variant	Intron 3 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.460 AC: 69767 AN: 151772 Hom.: 16209 Cov.: 31

Gnomad AFR AF: 0.534

Gnomad AMI AF: 0.302

Gnomad AMR AF: 0.458

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.474

Gnomad SAS AF: 0.424

Gnomad FIN AF: 0.426

Gnomad MID AF: 0.323

Gnomad NFE AF: 0.430

Gnomad OTH AF: 0.428

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

GnomAD4 genome AF: 0.460 AC: 69846 AN: 151890 Hom.: 16238 Cov.: 31 AF XY: 0.457 AC XY: 33922 AN XY: 74230

African (AFR) AF: 0.535 AC: 22148 AN: 41400

American (AMR) AF: 0.458 AC: 6990 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1258 AN: 3470

East Asian (EAS) AF: 0.474 AC: 2437 AN: 5138

South Asian (SAS) AF: 0.424 AC: 2034 AN: 4802

European-Finnish (FIN) AF: 0.426 AC: 4512 AN: 10582

Middle Eastern (MID) AF: 0.333 AC: 98 AN: 294

European-Non Finnish (NFE) AF: 0.430 AC: 29194 AN: 67920

Other (OTH) AF: 0.428 AC: 900 AN: 2104

Alfa AF: 0.448 Hom.: 2622

Bravo AF: 0.467

Asia WGS AF: 0.463 AC: 1614 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	0.27
DANN	Benign	0.79
PhyloP100		-2.7
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: rs1730240; hg19: chr3-25607513;