rs9840225

Variant names:

• chr3-25139539-G-A
• rs9840225
• NM_001290216.3:c.-279-34580G>A

Variant summary

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

The NM_001290216.3(RARB):​c.-279-34580G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.111 in 152,060 control chromosomes in the GnomAD database, including 976 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 0.11 (976 hom., cov: 33)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.843
• Publications: 1 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.131 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_001290216.3	c.-279-34580G>A		intron_variant	Intron 3 of 10		NP_001277145.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000383772.9	c.-280+7331G>A		intron_variant	Intron 4 of 11	5		ENSP00000373282.5
RARB	ENST00000686715.1	c.-279-34580G>A		intron_variant	Intron 4 of 11			ENSP00000510539.1
RARB	ENST00000687353.1	c.-279-34580G>A		intron_variant	Intron 5 of 12			ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.111 AC: 16902 AN: 151942 Hom.: 971 Cov.: 33

Gnomad AFR AF: 0.107

Gnomad AMI AF: 0.117

Gnomad AMR AF: 0.0771

Gnomad ASJ AF: 0.0734

Gnomad EAS AF: 0.00135

Gnomad SAS AF: 0.0665

Gnomad FIN AF: 0.126

Gnomad MID AF: 0.0696

Gnomad NFE AF: 0.133

Gnomad OTH AF: 0.105

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

GnomAD4 genome AF: 0.111 AC: 16918 AN: 152060 Hom.: 976 Cov.: 33 AF XY: 0.109 AC XY: 8069 AN XY: 74322

African (AFR) AF: 0.107 AC: 4458 AN: 41492

American (AMR) AF: 0.0770 AC: 1176 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.0734 AC: 255 AN: 3472

East Asian (EAS) AF: 0.00135 AC: 7 AN: 5180

South Asian (SAS) AF: 0.0662 AC: 319 AN: 4822

European-Finnish (FIN) AF: 0.126 AC: 1334 AN: 10566

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

European-Non Finnish (NFE) AF: 0.133 AC: 9023 AN: 67942

Other (OTH) AF: 0.103 AC: 218 AN: 2108

Alfa AF: 0.118 Hom.: 142

Bravo AF: 0.107

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	0.20
DANN	Benign	0.21
PhyloP100		-0.84

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs9840225; hg19: chr3-25181030;