NM_000965.5:c.448+16234T>A

Variant names:

• chr3-25517557-T-A
• rs1153592
• NM_000965.5:c.448+16234T>A

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+16234T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.249 in 152,016 control chromosomes in the GnomAD database, including 6,195 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 0.25 (6195 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.28
• 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=-0.94).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.453 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.448+16234T>A		intron_variant	Intron 3 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.448+16234T>A		intron_variant	Intron 3 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.249 AC: 37861 AN: 151898 Hom.: 6179 Cov.: 32

Gnomad AFR AF: 0.430

Gnomad AMI AF: 0.100

Gnomad AMR AF: 0.333

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.470

Gnomad SAS AF: 0.135

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.146

Gnomad NFE AF: 0.137

Gnomad OTH AF: 0.231

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

GnomAD4 genome AF: 0.249 AC: 37919 AN: 152016 Hom.: 6195 Cov.: 32 AF XY: 0.251 AC XY: 18651 AN XY: 74330

African (AFR) AF: 0.429 AC: 17792 AN: 41428

American (AMR) AF: 0.334 AC: 5102 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3468

East Asian (EAS) AF: 0.469 AC: 2413 AN: 5144

South Asian (SAS) AF: 0.133 AC: 643 AN: 4824

European-Finnish (FIN) AF: 0.150 AC: 1587 AN: 10594

Middle Eastern (MID) AF: 0.153 AC: 45 AN: 294

European-Non Finnish (NFE) AF: 0.137 AC: 9321 AN: 67970

Other (OTH) AF: 0.238 AC: 501 AN: 2108

Alfa AF: 0.205 Hom.: 537

Bravo AF: 0.278

Asia WGS AF: 0.324 AC: 1122 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.94
CADD	Benign	0.27
DANN	Benign	0.78
PhyloP100		-1.3
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: rs1153592; hg19: chr3-25559048;