3-25483077-A-G

Variant names:

• chr3-25483077-A-G
• rs6550982
• NM_000965.5:c.307-18105A>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.307-18105A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.493 in 152,026 control chromosomes in the GnomAD database, including 20,286 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 0.49 (20286 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.971
• 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: 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=-0.87).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.632 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.307-18105A>G		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.328-18105A>G		intron	N/A	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.178-18105A>G		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.307-18105A>G		intron	N/A	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.-30-18105A>G		intron	N/A	ENSP00000398840.2	P10826-3
	RARB	ENST00000458646.2	TSL:1	c.-30-18105A>G		intron	N/A	ENSP00000391391.1	P10826-3

Frequencies

GnomAD3 genomes AF: 0.493 AC: 74923 AN: 151908 Hom.: 20269 Cov.: 32

Gnomad AFR AF: 0.263

Gnomad AMI AF: 0.758

Gnomad AMR AF: 0.487

Gnomad ASJ AF: 0.576

Gnomad EAS AF: 0.427

Gnomad SAS AF: 0.650

Gnomad FIN AF: 0.583

Gnomad MID AF: 0.519

Gnomad NFE AF: 0.607

Gnomad OTH AF: 0.490

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

GnomAD4 genome AF: 0.493 AC: 74959 AN: 152026 Hom.: 20286 Cov.: 32 AF XY: 0.494 AC XY: 36739 AN XY: 74298

African (AFR) AF: 0.263 AC: 10911 AN: 41458

American (AMR) AF: 0.487 AC: 7435 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.576 AC: 1999 AN: 3472

East Asian (EAS) AF: 0.427 AC: 2208 AN: 5166

South Asian (SAS) AF: 0.651 AC: 3140 AN: 4822

European-Finnish (FIN) AF: 0.583 AC: 6148 AN: 10546

Middle Eastern (MID) AF: 0.517 AC: 152 AN: 294

European-Non Finnish (NFE) AF: 0.607 AC: 41235 AN: 67980

Other (OTH) AF: 0.493 AC: 1041 AN: 2112

Alfa AF: 0.565 Hom.: 5063

Bravo AF: 0.471

Asia WGS AF: 0.495 AC: 1723 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.062
DANN	Benign	0.49
PhyloP100		-0.97
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: rs6550982; hg19: chr3-25524568;