rs3773438

Variant names:

• chr3-25576350-C-T
• rs3773438
• NM_000965.5:c.610-4196C>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.631-4196C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 152,206 control chromosomes in the GnomAD database, including 1,242 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 0.12 (1242 hom., cov: 32)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0550
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.236 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	NM_000965.5	MANE Select	c.610-4196C>T		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.631-4196C>T		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.481-4196C>T		intron	N/A	NP_001277229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000330688.9	TSL:1 MANE Select	c.610-4196C>T		intron	N/A	ENSP00000332296.4
	RARB	ENST00000437042.7	TSL:1	c.274-4196C>T		intron	N/A	ENSP00000398840.2
	RARB	ENST00000458646.2	TSL:1	c.274-4196C>T		intron	N/A	ENSP00000391391.1

Frequencies

GnomAD3 genomes AF: 0.121 AC: 18371 AN: 152088 Hom.: 1246 Cov.: 32

Gnomad AFR AF: 0.0652

Gnomad AMI AF: 0.184

Gnomad AMR AF: 0.119

Gnomad ASJ AF: 0.188

Gnomad EAS AF: 0.247

Gnomad SAS AF: 0.146

Gnomad FIN AF: 0.144

Gnomad MID AF: 0.149

Gnomad NFE AF: 0.135

Gnomad OTH AF: 0.129

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

GnomAD4 genome AF: 0.121 AC: 18375 AN: 152206 Hom.: 1242 Cov.: 32 AF XY: 0.122 AC XY: 9096 AN XY: 74406

African (AFR) AF: 0.0653 AC: 2713 AN: 41542

American (AMR) AF: 0.119 AC: 1824 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.188 AC: 653 AN: 3468

East Asian (EAS) AF: 0.247 AC: 1277 AN: 5168

South Asian (SAS) AF: 0.146 AC: 703 AN: 4826

European-Finnish (FIN) AF: 0.144 AC: 1528 AN: 10588

Middle Eastern (MID) AF: 0.160 AC: 47 AN: 294

European-Non Finnish (NFE) AF: 0.135 AC: 9195 AN: 67992

Other (OTH) AF: 0.126 AC: 267 AN: 2112

Alfa AF: 0.138 Hom.: 530

Bravo AF: 0.117

Asia WGS AF: 0.195 AC: 681 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	2.7
DANN	Benign	0.60
PhyloP100		0.055
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: rs3773438; hg19: chr3-25617841;