9-74630349-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_006914.4(RORB):c.75C>T(p.Ile25=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0049 in 1,612,784 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0047 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0049 (37 hom.)
• Consequence: RORB NM_006914.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.55

Genes affected

RORB (HGNC:10259): (RAR related orphan receptor B) The protein encoded by this gene is a member of the NR1 subfamily of nuclear hormone receptors. It is a DNA-binding protein that can bind as a monomer or as a homodimer to hormone response elements upstream of several genes to enhance the expression of those genes. The encoded protein has been shown to interact with NM23-2, a nucleoside diphosphate kinase involved in organogenesis and differentiation, and to help regulate the expression of some genes involved in circadian rhythm. [provided by RefSeq, Feb 2014]

ACMG classification

Verdict is Benign. Variant got -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 9-74630349-C-T is Benign according to our data. Variant chr9-74630349-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 782753.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.55 with no splicing effect.
• BS2: High AC in GnomAd at 711 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RORB	NM_006914.4	c.75C>T	p.Ile25=	synonymous_variant	2/10	ENST00000376896.8
RORB	NM_001365023.1	c.108C>T	p.Ile36=	synonymous_variant	2/10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RORB	ENST00000376896.8	c.75C>T	p.Ile25=	synonymous_variant	2/10	1	NM_006914.4	P1
RORB	ENST00000396204.2	c.108C>T	p.Ile36=	synonymous_variant	2/10	1

Frequencies

GnomAD3 genomes AF: 0.00467 AC: 711 AN: 152172 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00101

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00616

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.0173

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00545

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00521 AC: 1306 AN: 250716 Hom.: 7 AF XY: 0.00500 AC XY: 678 AN XY: 135490

Gnomad AFR exome AF: 0.00105

Gnomad AMR exome AF: 0.00335

Gnomad ASJ exome AF: 0.00238

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00111

Gnomad FIN exome AF: 0.0172

Gnomad NFE exome AF: 0.00629

Gnomad OTH exome AF: 0.00492

GnomAD4 exome AF: 0.00493 AC: 7198 AN: 1460494 Hom.: 37 Cov.: 32 AF XY: 0.00484 AC XY: 3513 AN XY: 726546

Gnomad4 AFR exome AF: 0.000688

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00329

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00112

Gnomad4 FIN exome AF: 0.0191

Gnomad4 NFE exome AF: 0.00499

Gnomad4 OTH exome AF: 0.00456

GnomAD4 genome AF: 0.00467 AC: 711 AN: 152290 Hom.: 2 Cov.: 33 AF XY: 0.00505 AC XY: 376 AN XY: 74462

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00615

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.0173

Gnomad4 NFE AF: 0.00545

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00433 Hom.: 2

Bravo AF: 0.00335

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00586

EpiControl AF: 0.00470

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	RORB: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	14
Dann	Benign	0.82

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs41307459; hg19: chr9-77245265;