3-25597903-T-G

Variant names:

• chr3-25597903-T-G
• rs1058378
• NM_000965.5:c.*1287T>G

Variant summary

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

The NM_000965.5(RARB):​c.*1287T>G variant causes a 3 prime UTR change. The variant allele was found at a frequency of 0.208 in 153,250 control chromosomes in the GnomAD database, including 5,297 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 0.21 (5284 hom., cov: 32)
  • Exomes 𝑓: 0.11 (13 hom.)
• Consequence: RARB NM_000965.5 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 7.06
• Publications: 12 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]

TOP2B (HGNC:11990): (DNA topoisomerase II beta) This gene encodes a DNA topoisomerase, an enzyme that controls and alters the topologic states of DNA during transcription. This nuclear enzyme is involved in processes such as chromosome condensation, chromatid separation, and the relief of torsional stress that occurs during DNA transcription and replication. It catalyzes the transient breaking and rejoining of two strands of duplex DNA which allows the strands to pass through one another, thus altering the topology of DNA. Two forms of this enzyme exist as likely products of a gene duplication event. The gene encoding this form, beta, is localized to chromosome 3 and the alpha form is localized to chromosome 17. The gene encoding this enzyme functions as the target for several anticancer agents and a variety of mutations in this gene have been associated with the development of drug resistance. Reduced activity of this enzyme may also play a role in ataxia-telangiectasia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

TOP2B Gene-Disease associations (from GenCC):

• B-cell immunodeficiency, distal limb anomalies, and urogenital malformations

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, ClinGen
• neurodevelopmental disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.463 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RARB	NM_000965.5	c.*1287T>G		3_prime_UTR_variant	Exon 8 of 8	ENST00000330688.9	NP_000956.2
TOP2B	NM_001330700.2	c.*404A>C		downstream_gene_variant		ENST00000264331.9	NP_001317629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RARB	ENST00000330688.9	c.*1287T>G		3_prime_UTR_variant	Exon 8 of 8	1	NM_000965.5	ENSP00000332296.4
TOP2B	ENST00000264331.9	c.*404A>C		downstream_gene_variant		5	NM_001330700.2	ENSP00000264331.4

Frequencies

GnomAD3 genomes AF: 0.208 AC: 31652 AN: 151922 Hom.: 5270 Cov.: 32

Gnomad AFR AF: 0.468

Gnomad AMI AF: 0.104

Gnomad AMR AF: 0.168

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.116

Gnomad SAS AF: 0.137

Gnomad FIN AF: 0.0991

Gnomad MID AF: 0.131

Gnomad NFE AF: 0.0958

Gnomad OTH AF: 0.176

GnomAD4 exome AF: 0.107 AC: 129 AN: 1208 Hom.: 13 Cov.: 0 AF XY: 0.0997 AC XY: 61 AN XY: 612

African (AFR) AF: 0.471 AC: 16 AN: 34

American (AMR) AF: 0.192 AC: 5 AN: 26

Ashkenazi Jewish (ASJ) AF: 0.114 AC: 5 AN: 44

East Asian (EAS) AF: 0.0385 AC: 1 AN: 26

South Asian (SAS) AF: 0.00 AC: 0 AN: 12

European-Finnish (FIN) AF: 0.118 AC: 54 AN: 458

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 0.0725 AC: 40 AN: 552

Other (OTH) AF: 0.143 AC: 8 AN: 56

GnomAD4 genome AF: 0.209 AC: 31708 AN: 152042 Hom.: 5284 Cov.: 32 AF XY: 0.205 AC XY: 15247 AN XY: 74366

African (AFR) AF: 0.468 AC: 19393 AN: 41394

American (AMR) AF: 0.168 AC: 2560 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 432 AN: 3472

East Asian (EAS) AF: 0.117 AC: 604 AN: 5184

South Asian (SAS) AF: 0.136 AC: 654 AN: 4820

European-Finnish (FIN) AF: 0.0991 AC: 1050 AN: 10598

Middle Eastern (MID) AF: 0.127 AC: 37 AN: 292

European-Non Finnish (NFE) AF: 0.0958 AC: 6515 AN: 67990

Other (OTH) AF: 0.175 AC: 369 AN: 2108

Alfa AF: 0.114 Hom.: 1783

Bravo AF: 0.228

Asia WGS AF: 0.153 AC: 533 AN: 3476

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
CADD	Benign	17
DANN	Benign	0.90
PhyloP100		7.1
Mutation Taster		=98/2	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: rs1058378; hg19: chr3-25639394;