3-25567085-C-T

Variant names:

• chr3-25567085-C-T
• rs1286729
• NM_000965.5:c.449-2673C>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.449-2673C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.081 in 152,160 control chromosomes in the GnomAD database, including 646 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 0.081 (646 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.646
• Publications: 9 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=-0.86).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 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.449-2673C>T		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.470-2673C>T		intron	N/A	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.320-2673C>T		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.449-2673C>T		intron	N/A	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.113-2673C>T		intron	N/A	ENSP00000398840.2	P10826-3
	RARB	ENST00000458646.2	TSL:1	c.113-2673C>T		intron	N/A	ENSP00000391391.1	P10826-3

Frequencies

GnomAD3 genomes AF: 0.0811 AC: 12331 AN: 152042 Hom.: 644 Cov.: 32

Gnomad AFR AF: 0.0207

Gnomad AMI AF: 0.0647

Gnomad AMR AF: 0.108

Gnomad ASJ AF: 0.0491

Gnomad EAS AF: 0.0844

Gnomad SAS AF: 0.0962

Gnomad FIN AF: 0.112

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0642

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

GnomAD4 genome AF: 0.0810 AC: 12332 AN: 152160 Hom.: 646 Cov.: 32 AF XY: 0.0810 AC XY: 6023 AN XY: 74402

African (AFR) AF: 0.0207 AC: 858 AN: 41528

American (AMR) AF: 0.107 AC: 1643 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0491 AC: 170 AN: 3464

East Asian (EAS) AF: 0.0842 AC: 435 AN: 5166

South Asian (SAS) AF: 0.0967 AC: 466 AN: 4818

European-Finnish (FIN) AF: 0.112 AC: 1185 AN: 10576

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.108 AC: 7375 AN: 68004

Other (OTH) AF: 0.0645 AC: 136 AN: 2108

Alfa AF: 0.0991 Hom.: 1465

Bravo AF: 0.0793

Asia WGS AF: 0.0780 AC: 271 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	1.0
DANN	Benign	0.58
PhyloP100		-0.65
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: rs1286729; hg19: chr3-25608576;