NM_000965.5:c.448+7929C>T

Variant names:

• chr3-25509252-C-T
• rs1881705
• NM_000965.5:c.448+7929C>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+7929C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.532 in 151,980 control chromosomes in the GnomAD database, including 23,328 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 0.53 (23328 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.582
• Publications: 4 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=-0.88).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.745 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.448+7929C>T		intron	N/A	NP_000956.2
	RARB	NM_001290216.3		c.469+7929C>T		intron	N/A	NP_001277145.1
	RARB	NM_001290300.2		c.319+7929C>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.448+7929C>T		intron	N/A	ENSP00000332296.4
	RARB	ENST00000437042.7	TSL:1	c.112+7929C>T		intron	N/A	ENSP00000398840.2
	RARB	ENST00000458646.2	TSL:1	c.112+7929C>T		intron	N/A	ENSP00000391391.1

Frequencies

GnomAD3 genomes AF: 0.532 AC: 80806 AN: 151864 Hom.: 23338 Cov.: 32

Gnomad AFR AF: 0.297

Gnomad AMI AF: 0.791

Gnomad AMR AF: 0.532

Gnomad ASJ AF: 0.717

Gnomad EAS AF: 0.509

Gnomad SAS AF: 0.766

Gnomad FIN AF: 0.632

Gnomad MID AF: 0.729

Gnomad NFE AF: 0.630

Gnomad OTH AF: 0.569

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

GnomAD4 genome AF: 0.532 AC: 80812 AN: 151980 Hom.: 23328 Cov.: 32 AF XY: 0.536 AC XY: 39817 AN XY: 74282

African (AFR) AF: 0.297 AC: 12306 AN: 41472

American (AMR) AF: 0.532 AC: 8120 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.717 AC: 2488 AN: 3472

East Asian (EAS) AF: 0.509 AC: 2617 AN: 5138

South Asian (SAS) AF: 0.765 AC: 3697 AN: 4830

European-Finnish (FIN) AF: 0.632 AC: 6663 AN: 10550

Middle Eastern (MID) AF: 0.726 AC: 212 AN: 292

European-Non Finnish (NFE) AF: 0.630 AC: 42799 AN: 67944

Other (OTH) AF: 0.565 AC: 1190 AN: 2108

Alfa AF: 0.599 Hom.: 22090

Bravo AF: 0.509

Asia WGS AF: 0.589 AC: 2051 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.40
DANN	Benign	0.56
PhyloP100		-0.58
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: rs1881705; hg19: chr3-25550743;