9-74497978-T-C

Variant names:

• chr9-74497978-T-C
• rs2117998071
• NM_006914.4:c.2T>C

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_006914.4(RORB):​c.2T>C​(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. 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)
• Consequence: RORB NM_006914.4 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.46
• Publications: 0 publications found

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]

RORB-AS1 (HGNC:49803): (RORB antisense RNA 1)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 19 pathogenic variants. Next in-frame start position is after 75 codons. Genomic position: 74634760. Lost 0.162 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORB	NM_006914.4	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	ENST00000376896.8	NP_008845.2
RORB-AS1	NR_125791.1	n.312+264A>G		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 10	1	NM_006914.4	ENSP00000366093.2
RORB-AS1	ENST00000417576.2	n.886+264A>G		intron_variant	Intron 1 of 2	5
RORB-AS1	ENST00000773819.1	n.124+264A>G		intron_variant	Intron 1 of 4
RORB-AS1	ENST00000773823.1	n.144+264A>G		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jun 30, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant in a gene for which loss-of-function is not a known mechanism of disease; Has not been previously published as pathogenic or benign to our knowledge; Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Benign	0.085
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.040	D
PhyloP100		4.5
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.52
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0090	D
Vest4		0.94
MutPred		0.94		Gain of catalytic residue at M1 (P = 0.0161);
MVP		0.26
ClinPred		0.86	D
GERP RS		5.4
gMVP		0.20
Mutation Taster		=14/186	disease causing

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: rs2117998071; hg19: chr9-77112894;