rs17016566

Variant names:

• chr3-25504728-C-G
• rs17016566
• NM_000965.5:c.448+3405C>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+3405C>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.131 in 150,434 control chromosomes in the GnomAD database, including 1,973 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 0.13 (1973 hom., cov: 31)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.364
• 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=-0.95).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.279 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.448+3405C>G		intron_variant	Intron 3 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.448+3405C>G		intron_variant	Intron 3 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.131 AC: 19636 AN: 150370 Hom.: 1972 Cov.: 31

Gnomad AFR AF: 0.284

Gnomad AMI AF: 0.0714

Gnomad AMR AF: 0.0825

Gnomad ASJ AF: 0.0584

Gnomad EAS AF: 0.105

Gnomad SAS AF: 0.0661

Gnomad FIN AF: 0.0754

Gnomad MID AF: 0.0752

Gnomad NFE AF: 0.0695

Gnomad OTH AF: 0.112

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

GnomAD4 genome AF: 0.131 AC: 19662 AN: 150434 Hom.: 1973 Cov.: 31 AF XY: 0.129 AC XY: 9477 AN XY: 73332

African (AFR) AF: 0.284 AC: 11565 AN: 40766

American (AMR) AF: 0.0826 AC: 1247 AN: 15098

Ashkenazi Jewish (ASJ) AF: 0.0584 AC: 202 AN: 3460

East Asian (EAS) AF: 0.105 AC: 536 AN: 5120

South Asian (SAS) AF: 0.0665 AC: 318 AN: 4782

European-Finnish (FIN) AF: 0.0754 AC: 759 AN: 10066

Middle Eastern (MID) AF: 0.0780 AC: 22 AN: 282

European-Non Finnish (NFE) AF: 0.0695 AC: 4716 AN: 67872

Other (OTH) AF: 0.112 AC: 232 AN: 2078

Alfa AF: 0.108 Hom.: 177

Bravo AF: 0.138

Asia WGS AF: 0.0980 AC: 343 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	0.45
DANN	Benign	0.54
PhyloP100		-0.36
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: rs17016566; hg19: chr3-25546219;