9-74497979-G-A

Variant names:

• chr9-74497979-G-A
• NM_006914.4:c.3G>A

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_006914.4(RORB):​c.3G>A​(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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RORB NM_006914.4 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 5.60
• 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 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 17 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
• PP5: Variant 9-74497979-G-A is Pathogenic according to our data. Variant chr9-74497979-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 3790175.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORB	NM_006914.4	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	ENST00000376896.8	NP_008845.2
RORB-AS1	NR_125791.1	n.312+263C>T		intron_variant	Intron 1 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORB	ENST00000376896.8	c.3G>A	p.Met1?	start_lost	Exon 1 of 10	1	NM_006914.4	ENSP00000366093.2
RORB-AS1	ENST00000417576.2	n.886+263C>T		intron_variant	Intron 1 of 2	5
RORB-AS1	ENST00000773819.1	n.124+263C>T		intron_variant	Intron 1 of 4
RORB-AS1	ENST00000773823.1	n.144+263C>T		intron_variant	Intron 1 of 3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Mar 07, 2025

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.3G>A (p.M1?) alteration is located in coding exon 1 of the RORB gene and consists of a G to A substitution at nucleotide position 1. This alters the methionine residue at the initiation codon (ATG). Sequence variations that modify the initiation codon are expected to result in either loss of translation initiation, N-terminal truncation, or cause a shift in the mRNA reading frame. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). Based on the available evidence, this alteration is classified as likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Benign	23
DANN	Benign	0.96
Eigen	Benign	0.0064
Eigen_PC	Benign	0.20
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.37	T
PhyloP100		5.6
PROVEAN	Benign	-0.50	N
REVEL	Uncertain	0.46
Sift	Benign	0.50	T
Sift4G	Benign	1.0	T
Vest4		0.93
MutPred		0.95		Gain of catalytic residue at M1 (P = 0.0327);
MVP		0.95
ClinPred		0.45	T
GERP RS		5.4
gMVP		0.17
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

hg19: chr9-77112895;