3-25129806-T-C

Variant names:

• chr3-25129806-T-C
• rs11129182
• NM_001290216.3:c.-279-44313T>C

Variant summary

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

The NM_001290216.3(RARB):​c.-279-44313T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.823 in 151,998 control chromosomes in the GnomAD database, including 51,535 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 0.82 (51535 hom., cov: 32)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.26
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.844 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_001290216.3	c.-279-44313T>C		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.-327-2355T>C		intron_variant	Intron 3 of 11	5		ENSP00000373282.5
RARB	ENST00000686715.1	c.-279-44313T>C		intron_variant	Intron 4 of 11			ENSP00000510539.1
RARB	ENST00000687353.1	c.-279-44313T>C		intron_variant	Intron 5 of 12			ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.822 AC: 124919 AN: 151880 Hom.: 51491 Cov.: 32

Gnomad AFR AF: 0.777

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.853

Gnomad ASJ AF: 0.902

Gnomad EAS AF: 0.810

Gnomad SAS AF: 0.764

Gnomad FIN AF: 0.781

Gnomad MID AF: 0.794

Gnomad NFE AF: 0.850

Gnomad OTH AF: 0.834

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

GnomAD4 genome AF: 0.823 AC: 125020 AN: 151998 Hom.: 51535 Cov.: 32 AF XY: 0.819 AC XY: 60811 AN XY: 74274

African (AFR) AF: 0.777 AC: 32222 AN: 41476

American (AMR) AF: 0.853 AC: 13004 AN: 15244

Ashkenazi Jewish (ASJ) AF: 0.902 AC: 3130 AN: 3470

East Asian (EAS) AF: 0.810 AC: 4172 AN: 5152

South Asian (SAS) AF: 0.765 AC: 3691 AN: 4822

European-Finnish (FIN) AF: 0.781 AC: 8242 AN: 10556

Middle Eastern (MID) AF: 0.799 AC: 235 AN: 294

European-Non Finnish (NFE) AF: 0.850 AC: 57736 AN: 67958

Other (OTH) AF: 0.834 AC: 1763 AN: 2114

Alfa AF: 0.839 Hom.: 36412

Bravo AF: 0.826

Asia WGS AF: 0.787 AC: 2730 AN: 3468

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.91
DANN	Benign	0.85
PhyloP100		-1.3

Splicing

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

Other links and lift over

dbSNP: rs11129182; hg19: chr3-25171297;