chr3-25450477-A-G

Variant names:

• chr3-25450477-A-G
• rs6793694
• NM_000965.5:c.158-10716A>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.158-10716A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.664 in 151,970 control chromosomes in the GnomAD database, including 33,848 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 0.66 (33848 hom., cov: 31)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0620
• Publications: 7 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=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.797 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.158-10716A>G		intron_variant	Intron 1 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.158-10716A>G		intron_variant	Intron 1 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.663 AC: 100736 AN: 151852 Hom.: 33800 Cov.: 31

Gnomad AFR AF: 0.730

Gnomad AMI AF: 0.842

Gnomad AMR AF: 0.611

Gnomad ASJ AF: 0.700

Gnomad EAS AF: 0.817

Gnomad SAS AF: 0.624

Gnomad FIN AF: 0.573

Gnomad MID AF: 0.687

Gnomad NFE AF: 0.635

Gnomad OTH AF: 0.678

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

GnomAD4 genome AF: 0.664 AC: 100835 AN: 151970 Hom.: 33848 Cov.: 31 AF XY: 0.661 AC XY: 49071 AN XY: 74230

African (AFR) AF: 0.730 AC: 30259 AN: 41452

American (AMR) AF: 0.611 AC: 9331 AN: 15272

Ashkenazi Jewish (ASJ) AF: 0.700 AC: 2426 AN: 3468

East Asian (EAS) AF: 0.818 AC: 4213 AN: 5150

South Asian (SAS) AF: 0.623 AC: 2995 AN: 4806

European-Finnish (FIN) AF: 0.573 AC: 6044 AN: 10546

Middle Eastern (MID) AF: 0.694 AC: 204 AN: 294

European-Non Finnish (NFE) AF: 0.635 AC: 43162 AN: 67958

Other (OTH) AF: 0.679 AC: 1433 AN: 2112

Alfa AF: 0.641 Hom.: 44394

Bravo AF: 0.670

Asia WGS AF: 0.710 AC: 2470 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	3.4
DANN	Benign	0.53
PhyloP100		0.062
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: rs6793694; hg19: chr3-25491968;