rs755661

Variant names:

• chr3-25430549-T-C
• rs755661
• NM_000965.5:c.157+1661T>C

Variant summary

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

The NM_000965.5(RARB):​c.157+1661T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.549 in 152,020 control chromosomes in the GnomAD database, including 23,357 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 0.55 (23357 hom., cov: 33)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.91
• Publications: 5 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=-0.6).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.601 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.157+1661T>C		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.157+1661T>C		intron_variant	Intron 1 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.548 AC: 83312 AN: 151900 Hom.: 23330 Cov.: 33

Gnomad AFR AF: 0.607

Gnomad AMI AF: 0.475

Gnomad AMR AF: 0.486

Gnomad ASJ AF: 0.551

Gnomad EAS AF: 0.237

Gnomad SAS AF: 0.474

Gnomad FIN AF: 0.554

Gnomad MID AF: 0.601

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.555

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

GnomAD4 genome AF: 0.549 AC: 83394 AN: 152020 Hom.: 23357 Cov.: 33 AF XY: 0.546 AC XY: 40602 AN XY: 74310

African (AFR) AF: 0.607 AC: 25163 AN: 41434

American (AMR) AF: 0.485 AC: 7412 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.551 AC: 1913 AN: 3470

East Asian (EAS) AF: 0.237 AC: 1225 AN: 5176

South Asian (SAS) AF: 0.476 AC: 2293 AN: 4820

European-Finnish (FIN) AF: 0.554 AC: 5855 AN: 10568

Middle Eastern (MID) AF: 0.605 AC: 178 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37758 AN: 67976

Other (OTH) AF: 0.554 AC: 1167 AN: 2108

Alfa AF: 0.551 Hom.: 43757

Bravo AF: 0.545

Asia WGS AF: 0.385 AC: 1342 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	16
DANN	Benign	0.81
PhyloP100		1.9
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: rs755661; hg19: chr3-25472040;