chr9-74630300-C-T

Position:

• chr9-74630300-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP2 PP3

The NM_006914.4(RORB):​c.26C>T​(p.Pro9Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000685 in 1,460,918 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: RORB NM_006914.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.91

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), RORB. . Gene score misZ 3.0833 (greater than the threshold 3.09). Trascript score misZ 3.661 (greater than threshold 3.09). GenCC has associacion of gene with epilepsy, epilepsy, idiopathic generalized, susceptibility to, 15, complex neurodevelopmental disorder.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.814

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RORB	NM_006914.4	c.26C>T	p.Pro9Leu	missense_variant	2/10	ENST00000376896.8	NP_008845.2
RORB	NM_001365023.1	c.59C>T	p.Pro20Leu	missense_variant	2/10		NP_001351952.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.26C>T	p.Pro9Leu	missense_variant	2/10	1	NM_006914.4	ENSP00000366093	P1
RORB	ENST00000396204.2	c.59C>T	p.Pro20Leu	missense_variant	2/10	1		ENSP00000379507

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460918 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 726764

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jul 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.52	D
BayesDel_noAF	Pathogenic	0.51
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.57	.;D
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D
M_CAP	Uncertain	0.29	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	0.74	D
MutationAssessor	Benign	1.2	.;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.95	D
PROVEAN	Pathogenic	-9.3	D;D
REVEL	Pathogenic	0.85
Sift	Pathogenic	0.0	D;D
Sift4G	Benign	0.075	T;T
Polyphen		1.0	.;D
Vest4		0.75
MutPred		0.59		.;Gain of ubiquitination at K22 (P = 0.0497);
MVP		0.62
MPC		2.8
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.87
gMVP		0.79

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-77245216;