chr3-25561241-G-C

Variant names:

• chr3-25561241-G-C
• rs10510568
• NM_000965.5:c.449-8517G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000965.5(RARB):​c.449-8517G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.368 in 151,980 control chromosomes in the GnomAD database, including 10,709 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 0.37 (10709 hom., cov: 32)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0900
• 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=-0.83).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.487 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.449-8517G>C		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.449-8517G>C		intron_variant	Intron 3 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.367 AC: 55787 AN: 151862 Hom.: 10682 Cov.: 32

Gnomad AFR AF: 0.492

Gnomad AMI AF: 0.301

Gnomad AMR AF: 0.346

Gnomad ASJ AF: 0.265

Gnomad EAS AF: 0.395

Gnomad SAS AF: 0.187

Gnomad FIN AF: 0.308

Gnomad MID AF: 0.250

Gnomad NFE AF: 0.324

Gnomad OTH AF: 0.330

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

GnomAD4 genome AF: 0.368 AC: 55864 AN: 151980 Hom.: 10709 Cov.: 32 AF XY: 0.361 AC XY: 26804 AN XY: 74272

African (AFR) AF: 0.493 AC: 20402 AN: 41418

American (AMR) AF: 0.346 AC: 5282 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.265 AC: 920 AN: 3472

East Asian (EAS) AF: 0.394 AC: 2038 AN: 5170

South Asian (SAS) AF: 0.187 AC: 903 AN: 4822

European-Finnish (FIN) AF: 0.308 AC: 3248 AN: 10556

Middle Eastern (MID) AF: 0.259 AC: 76 AN: 294

European-Non Finnish (NFE) AF: 0.324 AC: 22019 AN: 67950

Other (OTH) AF: 0.333 AC: 703 AN: 2110

Alfa AF: 0.363 Hom.: 1317

Bravo AF: 0.380

Asia WGS AF: 0.313 AC: 1093 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	1.2
DANN	Benign	0.76
PhyloP100		0.090
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: rs10510568; hg19: chr3-25602732;