chr3-25528074-C-T

Variant names:

• chr3-25528074-C-T
• rs1153600
• NM_000965.5:c.448+26751C>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.448+26751C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.462 in 151,984 control chromosomes in the GnomAD database, including 18,880 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 0.46 (18880 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.932
• Publications: 5 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=-0.56).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.725 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.448+26751C>T		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.469+26751C>T		intron	N/A	NP_001277145.1	P10826-1
	RARB	NM_001290300.2		c.319+26751C>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.448+26751C>T		intron	N/A	ENSP00000332296.4	P10826-2
	RARB	ENST00000437042.7	TSL:1	c.112+26751C>T		intron	N/A	ENSP00000398840.2	P10826-3
	RARB	ENST00000458646.2	TSL:1	c.112+26751C>T		intron	N/A	ENSP00000391391.1	P10826-3

Frequencies

GnomAD3 genomes AF: 0.462 AC: 70134 AN: 151868 Hom.: 18828 Cov.: 32

Gnomad AFR AF: 0.732

Gnomad AMI AF: 0.269

Gnomad AMR AF: 0.542

Gnomad ASJ AF: 0.350

Gnomad EAS AF: 0.502

Gnomad SAS AF: 0.275

Gnomad FIN AF: 0.333

Gnomad MID AF: 0.386

Gnomad NFE AF: 0.319

Gnomad OTH AF: 0.424

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

GnomAD4 genome AF: 0.462 AC: 70248 AN: 151984 Hom.: 18880 Cov.: 32 AF XY: 0.460 AC XY: 34148 AN XY: 74268

African (AFR) AF: 0.732 AC: 30383 AN: 41490

American (AMR) AF: 0.542 AC: 8287 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.350 AC: 1214 AN: 3466

East Asian (EAS) AF: 0.501 AC: 2567 AN: 5124

South Asian (SAS) AF: 0.274 AC: 1320 AN: 4818

European-Finnish (FIN) AF: 0.333 AC: 3511 AN: 10552

Middle Eastern (MID) AF: 0.398 AC: 117 AN: 294

European-Non Finnish (NFE) AF: 0.319 AC: 21700 AN: 67946

Other (OTH) AF: 0.429 AC: 904 AN: 2108

Alfa AF: 0.347 Hom.: 1436

Bravo AF: 0.498

Asia WGS AF: 0.429 AC: 1491 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
CADD	Benign	17
DANN	Benign	0.78
PhyloP100		0.93
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: rs1153600; hg19: chr3-25569565;