3-25444320-G-C

Variant names:

• chr3-25444320-G-C
• rs6799734
• NM_000965.5:c.157+15432G>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+15432G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.47 in 152,052 control chromosomes in the GnomAD database, including 17,899 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 0.47 (17899 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.940
• Publications: 6 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: AD, AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Baylor College of Medicine Research Center, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
• 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=-0.91).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.656 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000965.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	NM_000965.5	MANE Select	c.157+15432G>C		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.179-16873G>C		intron	N/A	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.29-16873G>C		intron	N/A	NP_001277229.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000330688.9	TSL:1 MANE Select	c.157+15432G>C		intron	N/A	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.-180+15789G>C		intron	N/A	ENSP00000398840.2	P10826-3
	RARB	ENST00000383772.9	TSL:5	c.179-16873G>C		intron	N/A	ENSP00000373282.5	P10826-1

Frequencies

GnomAD3 genomes AF: 0.469 AC: 71280 AN: 151934 Hom.: 17850 Cov.: 32

Gnomad AFR AF: 0.662

Gnomad AMI AF: 0.463

Gnomad AMR AF: 0.431

Gnomad ASJ AF: 0.414

Gnomad EAS AF: 0.449

Gnomad SAS AF: 0.361

Gnomad FIN AF: 0.424

Gnomad MID AF: 0.405

Gnomad NFE AF: 0.380

Gnomad OTH AF: 0.451

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

GnomAD4 genome AF: 0.470 AC: 71393 AN: 152052 Hom.: 17899 Cov.: 32 AF XY: 0.469 AC XY: 34843 AN XY: 74304

African (AFR) AF: 0.663 AC: 27465 AN: 41452

American (AMR) AF: 0.430 AC: 6570 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.414 AC: 1436 AN: 3468

East Asian (EAS) AF: 0.450 AC: 2329 AN: 5172

South Asian (SAS) AF: 0.361 AC: 1741 AN: 4818

European-Finnish (FIN) AF: 0.424 AC: 4489 AN: 10576

Middle Eastern (MID) AF: 0.425 AC: 125 AN: 294

European-Non Finnish (NFE) AF: 0.380 AC: 25857 AN: 67978

Other (OTH) AF: 0.454 AC: 959 AN: 2112

Alfa AF: 0.299 Hom.: 744

Bravo AF: 0.483

Asia WGS AF: 0.448 AC: 1559 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	1.9
DANN	Benign	0.52
PhyloP100		-0.94
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: rs6799734; hg19: chr3-25485811;