rs1656463

Variant names:

• chr3-25576668-G-A
• rs1656463
• NM_000965.5:c.610-3878G>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.610-3878G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.133 in 152,142 control chromosomes in the GnomAD database, including 1,555 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 0.13 (1555 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.81
• Publications: 11 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=-0.94).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.173 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.610-3878G>A		intron_variant	Intron 4 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.610-3878G>A		intron_variant	Intron 4 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.133 AC: 20192 AN: 152026 Hom.: 1551 Cov.: 32

Gnomad AFR AF: 0.0559

Gnomad AMI AF: 0.0614

Gnomad AMR AF: 0.165

Gnomad ASJ AF: 0.0945

Gnomad EAS AF: 0.0893

Gnomad SAS AF: 0.123

Gnomad FIN AF: 0.162

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.175

Gnomad OTH AF: 0.131

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

GnomAD4 genome AF: 0.133 AC: 20201 AN: 152142 Hom.: 1555 Cov.: 32 AF XY: 0.131 AC XY: 9734 AN XY: 74378

African (AFR) AF: 0.0559 AC: 2323 AN: 41538

American (AMR) AF: 0.164 AC: 2510 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.0945 AC: 328 AN: 3472

East Asian (EAS) AF: 0.0891 AC: 460 AN: 5164

South Asian (SAS) AF: 0.124 AC: 597 AN: 4822

European-Finnish (FIN) AF: 0.162 AC: 1716 AN: 10588

Middle Eastern (MID) AF: 0.0714 AC: 21 AN: 294

European-Non Finnish (NFE) AF: 0.175 AC: 11906 AN: 67972

Other (OTH) AF: 0.135 AC: 284 AN: 2102

Alfa AF: 0.167 Hom.: 3889

Bravo AF: 0.131

Asia WGS AF: 0.0960 AC: 335 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.29
DANN	Benign	0.62
PhyloP100		-2.8
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: rs1656463; hg19: chr3-25618159;