3-25418006-T-C

Variant names:

• chr3-25418006-T-C
• rs7648325
• NM_001290216.3:c.179-43187T>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.179-43187T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.654 in 152,070 control chromosomes in the GnomAD database, including 33,415 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 0.65 (33415 hom., cov: 31)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0600
• Publications: 2 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=-0.98).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.802 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_001290216.3		c.179-43187T>C		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.29-43187T>C		intron	N/A	NP_001277229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000383772.9	TSL:5	c.179-43187T>C		intron	N/A	ENSP00000373282.5
	RARB	ENST00000686715.1		c.179-43187T>C		intron	N/A	ENSP00000510539.1
	RARB	ENST00000687353.1		c.179-43187T>C		intron	N/A	ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.654 AC: 99309 AN: 151950 Hom.: 33388 Cov.: 31

Gnomad AFR AF: 0.798

Gnomad AMI AF: 0.728

Gnomad AMR AF: 0.570

Gnomad ASJ AF: 0.610

Gnomad EAS AF: 0.823

Gnomad SAS AF: 0.691

Gnomad FIN AF: 0.487

Gnomad MID AF: 0.690

Gnomad NFE AF: 0.596

Gnomad OTH AF: 0.654

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

GnomAD4 genome AF: 0.654 AC: 99387 AN: 152070 Hom.: 33415 Cov.: 31 AF XY: 0.647 AC XY: 48066 AN XY: 74316

African (AFR) AF: 0.797 AC: 33093 AN: 41498

American (AMR) AF: 0.570 AC: 8708 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.610 AC: 2115 AN: 3470

East Asian (EAS) AF: 0.823 AC: 4237 AN: 5150

South Asian (SAS) AF: 0.690 AC: 3324 AN: 4820

European-Finnish (FIN) AF: 0.487 AC: 5151 AN: 10572

Middle Eastern (MID) AF: 0.690 AC: 203 AN: 294

European-Non Finnish (NFE) AF: 0.596 AC: 40517 AN: 67978

Other (OTH) AF: 0.654 AC: 1378 AN: 2108

Alfa AF: 0.614 Hom.: 3438

Bravo AF: 0.664

Asia WGS AF: 0.738 AC: 2569 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.98
CADD	Benign	2.7
DANN	Benign	0.79
PhyloP100		-0.060
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: rs7648325; hg19: chr3-25459497;