chr3-25439269-G-C

Variant names:

• chr3-25439269-G-C
• rs9834818
• NM_000965.5:c.157+10381G>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.157+10381G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.765 in 152,104 control chromosomes in the GnomAD database, including 44,886 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 0.77 (44886 hom., cov: 33)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0670
• Publications: 2 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=-0.97).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.822 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.157+10381G>C		intron_variant	Intron 1 of 7	ENST00000330688.9	NP_000956.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.157+10381G>C		intron_variant	Intron 1 of 7	1	NM_000965.5	ENSP00000332296.4

Frequencies

GnomAD3 genomes AF: 0.765 AC: 116311 AN: 151988 Hom.: 44863 Cov.: 33

Gnomad AFR AF: 0.673

Gnomad AMI AF: 0.905

Gnomad AMR AF: 0.761

Gnomad ASJ AF: 0.852

Gnomad EAS AF: 0.590

Gnomad SAS AF: 0.760

Gnomad FIN AF: 0.765

Gnomad MID AF: 0.880

Gnomad NFE AF: 0.828

Gnomad OTH AF: 0.813

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

GnomAD4 genome AF: 0.765 AC: 116384 AN: 152104 Hom.: 44886 Cov.: 33 AF XY: 0.761 AC XY: 56605 AN XY: 74356

African (AFR) AF: 0.673 AC: 27895 AN: 41454

American (AMR) AF: 0.761 AC: 11648 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.852 AC: 2956 AN: 3470

East Asian (EAS) AF: 0.589 AC: 3043 AN: 5168

South Asian (SAS) AF: 0.760 AC: 3656 AN: 4808

European-Finnish (FIN) AF: 0.765 AC: 8093 AN: 10582

Middle Eastern (MID) AF: 0.881 AC: 259 AN: 294

European-Non Finnish (NFE) AF: 0.828 AC: 56304 AN: 68008

Other (OTH) AF: 0.808 AC: 1705 AN: 2110

Alfa AF: 0.728 Hom.: 2197

Bravo AF: 0.761

Asia WGS AF: 0.693 AC: 2412 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.97
CADD	Benign	1.7
DANN	Benign	0.48
PhyloP100		0.067
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: rs9834818; hg19: chr3-25480760;