3-25513615-T-G

Variant names:

• chr3-25513615-T-G
• rs1303629
• NM_000965.5:c.448+12292T>G

Variant summary

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

The NM_000965.5(RARB):​c.448+12292T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.414 in 151,322 control chromosomes in the GnomAD database, including 18,653 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 0.41 (18653 hom., cov: 30)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.149
• 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=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.829 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000965.5. 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.448+12292T>G		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.469+12292T>G		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.319+12292T>G		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.448+12292T>G		intron	N/A	ENSP00000332296.4
	RARB	ENST00000437042.7	TSL:1	c.112+12292T>G		intron	N/A	ENSP00000398840.2
	RARB	ENST00000458646.2	TSL:1	c.112+12292T>G		intron	N/A	ENSP00000391391.1

Frequencies

GnomAD3 genomes AF: 0.413 AC: 62446 AN: 151208 Hom.: 18590 Cov.: 30

Gnomad AFR AF: 0.836

Gnomad AMI AF: 0.126

Gnomad AMR AF: 0.433

Gnomad ASJ AF: 0.214

Gnomad EAS AF: 0.490

Gnomad SAS AF: 0.156

Gnomad FIN AF: 0.204

Gnomad MID AF: 0.261

Gnomad NFE AF: 0.214

Gnomad OTH AF: 0.376

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

GnomAD4 genome AF: 0.414 AC: 62574 AN: 151322 Hom.: 18653 Cov.: 30 AF XY: 0.410 AC XY: 30292 AN XY: 73954

African (AFR) AF: 0.836 AC: 34336 AN: 41052

American (AMR) AF: 0.434 AC: 6590 AN: 15188

Ashkenazi Jewish (ASJ) AF: 0.214 AC: 742 AN: 3466

East Asian (EAS) AF: 0.489 AC: 2506 AN: 5126

South Asian (SAS) AF: 0.155 AC: 747 AN: 4810

European-Finnish (FIN) AF: 0.204 AC: 2145 AN: 10496

Middle Eastern (MID) AF: 0.264 AC: 77 AN: 292

European-Non Finnish (NFE) AF: 0.214 AC: 14517 AN: 67880

Other (OTH) AF: 0.380 AC: 799 AN: 2102

Alfa AF: 0.350 Hom.: 5234

Bravo AF: 0.459

Asia WGS AF: 0.373 AC: 1296 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	3.0
DANN	Benign	0.47
PhyloP100		-0.15
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: rs1303629; hg19: chr3-25555106;