NM_000965.5:c.306+13284A>T

Variant names:

• chr3-25474625-A-T
• rs17016462
• NM_000965.5:c.306+13284A>T

Variant summary

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

The NM_000965.5(RARB):​c.306+13284A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0308 in 152,310 control chromosomes in the GnomAD database, including 247 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 0.031 (247 hom., cov: 33)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.669
• 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: 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=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.244 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	NM_000965.5	MANE Select	c.306+13284A>T		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.327+13284A>T		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.177+13284A>T		intron	N/A	NP_001277229.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RARB	ENST00000330688.9	TSL:1 MANE Select	c.306+13284A>T		intron	N/A	ENSP00000332296.4
	RARB	ENST00000437042.7	TSL:1	c.-31+13284A>T		intron	N/A	ENSP00000398840.2
	RARB	ENST00000458646.2	TSL:1	c.-31+13284A>T		intron	N/A	ENSP00000391391.1

Frequencies

GnomAD3 genomes AF: 0.0309 AC: 4701 AN: 152192 Hom.: 246 Cov.: 33

Gnomad AFR AF: 0.0183

Gnomad AMI AF: 0.0208

Gnomad AMR AF: 0.0329

Gnomad ASJ AF: 0.0493

Gnomad EAS AF: 0.256

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.0591

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0152

Gnomad OTH AF: 0.0258

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

GnomAD4 genome AF: 0.0308 AC: 4691 AN: 152310 Hom.: 247 Cov.: 33 AF XY: 0.0346 AC XY: 2580 AN XY: 74474

African (AFR) AF: 0.0183 AC: 763 AN: 41590

American (AMR) AF: 0.0327 AC: 500 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 171 AN: 3470

East Asian (EAS) AF: 0.255 AC: 1317 AN: 5160

South Asian (SAS) AF: 0.0417 AC: 201 AN: 4822

European-Finnish (FIN) AF: 0.0591 AC: 627 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0152 AC: 1033 AN: 68034

Other (OTH) AF: 0.0269 AC: 57 AN: 2116

Alfa AF: 0.0190 Hom.: 3

Bravo AF: 0.0306

Asia WGS AF: 0.136 AC: 471 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	9.7
DANN	Benign	0.76
PhyloP100		0.67
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: rs17016462; hg19: chr3-25516116;