NM_000965.5:c.306+17750C>A

Variant names:

• chr3-25479091-C-A
• rs1529672
• NM_000965.5:c.306+17750C>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000965.5(RARB):​c.306+17750C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.192 in 151,908 control chromosomes in the GnomAD database, including 2,979 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 0.19 (2979 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.82
• Publications: 49 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 -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.22).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.336 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.306+17750C>A		intron_variant	Intron 2 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.306+17750C>A		intron_variant	Intron 2 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.192 AC: 29172 AN: 151792 Hom.: 2984 Cov.: 32

Gnomad AFR AF: 0.208

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.245

Gnomad ASJ AF: 0.127

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.130

Gnomad FIN AF: 0.203

Gnomad MID AF: 0.152

Gnomad NFE AF: 0.166

Gnomad OTH AF: 0.189

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

GnomAD4 genome AF: 0.192 AC: 29190 AN: 151908 Hom.: 2979 Cov.: 32 AF XY: 0.194 AC XY: 14428 AN XY: 74250

African (AFR) AF: 0.208 AC: 8622 AN: 41422

American (AMR) AF: 0.245 AC: 3743 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.127 AC: 440 AN: 3464

East Asian (EAS) AF: 0.350 AC: 1800 AN: 5150

South Asian (SAS) AF: 0.129 AC: 620 AN: 4804

European-Finnish (FIN) AF: 0.203 AC: 2128 AN: 10500

Middle Eastern (MID) AF: 0.156 AC: 46 AN: 294

European-Non Finnish (NFE) AF: 0.166 AC: 11296 AN: 67970

Other (OTH) AF: 0.190 AC: 400 AN: 2110

Alfa AF: 0.174 Hom.: 10007

Bravo AF: 0.201

Asia WGS AF: 0.247 AC: 854 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.22
CADD	Benign	17
DANN	Benign	0.72
PhyloP100		1.8
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: rs1529672; hg19: chr3-25520582;