rs3773445

Variant names:

• chr3-25571074-A-G
• rs3773445
• NM_000965.5:c.609+1156A>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.609+1156A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.461 in 151,776 control chromosomes in the GnomAD database, including 16,188 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 0.46 (16188 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.492
• 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=-0.92).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.514 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.609+1156A>G		intron_variant	Intron 4 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.609+1156A>G		intron_variant	Intron 4 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.461 AC: 69897 AN: 151656 Hom.: 16161 Cov.: 32

Gnomad AFR AF: 0.519

Gnomad AMI AF: 0.281

Gnomad AMR AF: 0.439

Gnomad ASJ AF: 0.386

Gnomad EAS AF: 0.466

Gnomad SAS AF: 0.456

Gnomad FIN AF: 0.427

Gnomad MID AF: 0.345

Gnomad NFE AF: 0.443

Gnomad OTH AF: 0.430

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

GnomAD4 genome AF: 0.461 AC: 69976 AN: 151776 Hom.: 16188 Cov.: 32 AF XY: 0.458 AC XY: 33991 AN XY: 74178

African (AFR) AF: 0.520 AC: 21536 AN: 41426

American (AMR) AF: 0.438 AC: 6698 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.386 AC: 1337 AN: 3462

East Asian (EAS) AF: 0.466 AC: 2392 AN: 5136

South Asian (SAS) AF: 0.455 AC: 2192 AN: 4816

European-Finnish (FIN) AF: 0.427 AC: 4485 AN: 10500

Middle Eastern (MID) AF: 0.354 AC: 104 AN: 294

European-Non Finnish (NFE) AF: 0.443 AC: 30071 AN: 67844

Other (OTH) AF: 0.429 AC: 905 AN: 2108

Alfa AF: 0.446 Hom.: 25589

Bravo AF: 0.465

Asia WGS AF: 0.474 AC: 1654 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	0.56
DANN	Benign	0.34
PhyloP100		-0.49
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: rs3773445; hg19: chr3-25612565;