rs12630816

Variant names:

• chr3-25426257-C-T
• rs12630816
• NM_001290216.3:c.179-34936C>T

Variant summary

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

The NM_001290216.3(RARB):​c.179-34936C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0522 in 152,210 control chromosomes in the GnomAD database, including 278 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 0.052 (278 hom., cov: 33)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.480
• Publications: 4 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=-0.49).
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.075 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_001290216.3	c.179-34936C>T		intron_variant	Intron 4 of 10		NP_001277145.1
RARB	NM_001290300.2	c.29-34936C>T		intron_variant	Intron 1 of 7		NP_001277229.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000383772.9	c.179-34936C>T		intron_variant	Intron 5 of 11	5		ENSP00000373282.5
RARB	ENST00000686715.1	c.179-34936C>T		intron_variant	Intron 5 of 11			ENSP00000510539.1
RARB	ENST00000687353.1	c.179-34936C>T		intron_variant	Intron 6 of 12			ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.0522 AC: 7939 AN: 152092 Hom.: 278 Cov.: 33

Gnomad AFR AF: 0.0125

Gnomad AMI AF: 0.255

Gnomad AMR AF: 0.0783

Gnomad ASJ AF: 0.0743

Gnomad EAS AF: 0.0632

Gnomad SAS AF: 0.0348

Gnomad FIN AF: 0.0500

Gnomad MID AF: 0.0854

Gnomad NFE AF: 0.0671

Gnomad OTH AF: 0.0585

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

GnomAD4 genome AF: 0.0522 AC: 7947 AN: 152210 Hom.: 278 Cov.: 33 AF XY: 0.0525 AC XY: 3906 AN XY: 74412

African (AFR) AF: 0.0124 AC: 517 AN: 41554

American (AMR) AF: 0.0787 AC: 1202 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.0743 AC: 258 AN: 3472

East Asian (EAS) AF: 0.0634 AC: 328 AN: 5174

South Asian (SAS) AF: 0.0348 AC: 168 AN: 4826

European-Finnish (FIN) AF: 0.0500 AC: 530 AN: 10590

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0671 AC: 4562 AN: 68006

Other (OTH) AF: 0.0579 AC: 122 AN: 2108

Alfa AF: 0.0639 Hom.: 295

Bravo AF: 0.0544

Asia WGS AF: 0.0430 AC: 152 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.49
CADD	Benign	11
DANN	Benign	0.76
PhyloP100		0.48
Mutation Taster		=100/0	polymorphism (auto)

Splicing

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

Other links and lift over

dbSNP: rs12630816; hg19: chr3-25467748;