3-25461378-T-G

Position:

• chr3-25461378-T-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000965.5(RARB):​c.306+37T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.115 in 1,604,214 control chromosomes in the GnomAD database, including 11,144 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.13 (1374 hom., cov: 32)
  • Exomes 𝑓: 0.11 (9770 hom.)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.210

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BP6: Variant 3-25461378-T-G is Benign according to our data. Variant chr3-25461378-T-G is described in ClinVar as [Benign]. Clinvar id is 1277051.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.179 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARB	NM_000965.5	c.306+37T>G		intron_variant		ENST00000330688.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARB	ENST00000330688.9	c.306+37T>G		intron_variant		1	NM_000965.5	P1

Frequencies

GnomAD3 genomes AF: 0.130 AC: 19819 AN: 152082 Hom.: 1371 Cov.: 32

Gnomad AFR AF: 0.182

Gnomad AMI AF: 0.0252

Gnomad AMR AF: 0.0927

Gnomad ASJ AF: 0.0853

Gnomad EAS AF: 0.117

Gnomad SAS AF: 0.140

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.139

Gnomad NFE AF: 0.110

Gnomad OTH AF: 0.127

GnomAD3 exomes AF: 0.114 AC: 27616 AN: 242730 Hom.: 1804 AF XY: 0.114 AC XY: 14942 AN XY: 130914

Gnomad AFR exome AF: 0.191

Gnomad AMR exome AF: 0.0640

Gnomad ASJ exome AF: 0.0930

Gnomad EAS exome AF: 0.0982

Gnomad SAS exome AF: 0.139

Gnomad FIN exome AF: 0.133

Gnomad NFE exome AF: 0.112

Gnomad OTH exome AF: 0.112

GnomAD4 exome AF: 0.113 AC: 164127 AN: 1452012 Hom.: 9770 Cov.: 32 AF XY: 0.113 AC XY: 81813 AN XY: 721544

Gnomad4 AFR exome AF: 0.188

Gnomad4 AMR exome AF: 0.0663

Gnomad4 ASJ exome AF: 0.0891

Gnomad4 EAS exome AF: 0.131

Gnomad4 SAS exome AF: 0.132

Gnomad4 FIN exome AF: 0.129

Gnomad4 NFE exome AF: 0.110

Gnomad4 OTH exome AF: 0.116

GnomAD4 genome AF: 0.130 AC: 19848 AN: 152202 Hom.: 1374 Cov.: 32 AF XY: 0.132 AC XY: 9798 AN XY: 74404

Gnomad4 AFR AF: 0.182

Gnomad4 AMR AF: 0.0928

Gnomad4 ASJ AF: 0.0853

Gnomad4 EAS AF: 0.118

Gnomad4 SAS AF: 0.139

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.110

Gnomad4 OTH AF: 0.126

Alfa AF: 0.129 Hom.: 246

Bravo AF: 0.129

Asia WGS AF: 0.145 AC: 502 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	May 15, 2021	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.71
DANN	Benign	0.41

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

Publications

LitVar

Other links and lift over

dbSNP: rs2067964; hg19: chr3-25502869;