3-25461360-G-A

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+19G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0449 in 1,610,062 control chromosomes in the GnomAD database, including 2,676 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.044 (291 hom., cov: 32)
  • Exomes 𝑓: 0.045 (2385 hom.)
• Consequence: RARB NM_000965.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.497

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=-0.82).
• BP6: Variant 3-25461360-G-A is Benign according to our data. Variant chr3-25461360-G-A is described in ClinVar as [Benign]. Clinvar id is 1274651.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.113 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RARB	NM_000965.5	c.306+19G>A		intron_variant		ENST00000330688.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RARB	ENST00000330688.9	c.306+19G>A		intron_variant		1	NM_000965.5	P1

Frequencies

GnomAD3 genomes AF: 0.0437 AC: 6653 AN: 152080 Hom.: 290 Cov.: 32

Gnomad AFR AF: 0.0116

Gnomad AMI AF: 0.0581

Gnomad AMR AF: 0.117

Gnomad ASJ AF: 0.0164

Gnomad EAS AF: 0.0536

Gnomad SAS AF: 0.106

Gnomad FIN AF: 0.0940

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0350

Gnomad OTH AF: 0.0456

GnomAD3 exomes AF: 0.0707 AC: 17446 AN: 246834 Hom.: 1067 AF XY: 0.0688 AC XY: 9166 AN XY: 133302

Gnomad AFR exome AF: 0.0113

Gnomad AMR exome AF: 0.179

Gnomad ASJ exome AF: 0.0177

Gnomad EAS exome AF: 0.0603

Gnomad SAS exome AF: 0.107

Gnomad FIN exome AF: 0.0983

Gnomad NFE exome AF: 0.0384

Gnomad OTH exome AF: 0.0601

GnomAD4 exome AF: 0.0450 AC: 65605 AN: 1457864 Hom.: 2385 Cov.: 32 AF XY: 0.0465 AC XY: 33713 AN XY: 725046

Gnomad4 AFR exome AF: 0.00956

Gnomad4 AMR exome AF: 0.173

Gnomad4 ASJ exome AF: 0.0181

Gnomad4 EAS exome AF: 0.0427

Gnomad4 SAS exome AF: 0.105

Gnomad4 FIN exome AF: 0.0978

Gnomad4 NFE exome AF: 0.0346

Gnomad4 OTH exome AF: 0.0438

GnomAD4 genome AF: 0.0438 AC: 6667 AN: 152198 Hom.: 291 Cov.: 32 AF XY: 0.0486 AC XY: 3618 AN XY: 74410

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.118

Gnomad4 ASJ AF: 0.0164

Gnomad4 EAS AF: 0.0534

Gnomad4 SAS AF: 0.106

Gnomad4 FIN AF: 0.0940

Gnomad4 NFE AF: 0.0350

Gnomad4 OTH AF: 0.0475

Alfa AF: 0.0369 Hom.: 23

Bravo AF: 0.0437

Asia WGS AF: 0.0810 AC: 282 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microphthalmia, syndromic 12 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

May 15, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
Cadd	Benign	4.8
Dann	Benign	0.46

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: rs77748152; hg19: chr3-25502851; COSMIC: COSV58067681;