3-25423517-C-A

Variant names:

• chr3-25423517-C-A
• rs922939
• NM_001290216.3:c.179-37676C>A

Variant summary

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

The NM_001290216.3(RARB):​c.179-37676C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.64 in 152,048 control chromosomes in the GnomAD database, including 31,414 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 0.64 (31414 hom., cov: 32)
• Consequence: RARB NM_001290216.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.435
• Publications: 8 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 = 0.777 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001290216.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	NM_001290216.3		c.179-37676C>A		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.29-37676C>A		intron	N/A	NP_001277229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000383772.9	TSL:5	c.179-37676C>A		intron	N/A	ENSP00000373282.5
	RARB	ENST00000686715.1		c.179-37676C>A		intron	N/A	ENSP00000510539.1
	RARB	ENST00000687353.1		c.179-37676C>A		intron	N/A	ENSP00000508588.1

Frequencies

GnomAD3 genomes AF: 0.640 AC: 97233 AN: 151930 Hom.: 31404 Cov.: 32

Gnomad AFR AF: 0.549

Gnomad AMI AF: 0.709

Gnomad AMR AF: 0.659

Gnomad ASJ AF: 0.663

Gnomad EAS AF: 0.797

Gnomad SAS AF: 0.689

Gnomad FIN AF: 0.688

Gnomad MID AF: 0.608

Gnomad NFE AF: 0.666

Gnomad OTH AF: 0.629

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

GnomAD4 genome AF: 0.640 AC: 97280 AN: 152048 Hom.: 31414 Cov.: 32 AF XY: 0.642 AC XY: 47718 AN XY: 74288

African (AFR) AF: 0.549 AC: 22736 AN: 41432

American (AMR) AF: 0.659 AC: 10066 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.663 AC: 2298 AN: 3468

East Asian (EAS) AF: 0.797 AC: 4131 AN: 5180

South Asian (SAS) AF: 0.689 AC: 3323 AN: 4820

European-Finnish (FIN) AF: 0.688 AC: 7266 AN: 10568

Middle Eastern (MID) AF: 0.606 AC: 177 AN: 292

European-Non Finnish (NFE) AF: 0.666 AC: 45309 AN: 67986

Other (OTH) AF: 0.628 AC: 1327 AN: 2112

Alfa AF: 0.654 Hom.: 51433

Bravo AF: 0.633

Asia WGS AF: 0.713 AC: 2474 AN: 3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.42
DANN	Benign	0.22
PhyloP100		-0.43
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs922939; hg19: chr3-25465008;