rs1469359718

Variant names:

• chr1-151807498-C-T
• rs1469359718
• NM_005060.4:c.1531G>A

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005060.4(RORC):​c.1531G>A​(p.Glu511Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000889 in 1,461,822 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000089 (0 hom.)
• Consequence: RORC NM_005060.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.13
• Publications: 2 publications found

Genes affected

RORC (HGNC:10260): (RAR related orphan receptor C) The protein encoded by this gene is a DNA-binding transcription factor and is a member of the NR1 subfamily of nuclear hormone receptors. The specific functions of this protein are not known; however, studies of a similar gene in mice have shown that this gene may be essential for lymphoid organogenesis and may play an important regulatory role in thymopoiesis. In addition, studies in mice suggest that the protein encoded by this gene may inhibit the expression of Fas ligand and IL2. Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

RORC Gene-Disease associations (from GenCC):

• autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency

  Inheritance: AR, AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, PanelApp Australia, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2824937).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005060.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORC	NM_005060.4	MANE Select	c.1531G>A	p.Glu511Lys	missense	Exon 11 of 11	NP_005051.2
	RORC	NM_001001523.2		c.1468G>A	p.Glu490Lys	missense	Exon 10 of 10	NP_001001523.1	P51449-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RORC	ENST00000318247.7	TSL:1 MANE Select	c.1531G>A	p.Glu511Lys	missense	Exon 11 of 11	ENSP00000327025.6	P51449-1
	RORC	ENST00000356728.11	TSL:1	c.1468G>A	p.Glu490Lys	missense	Exon 10 of 10	ENSP00000349164.6	P51449-2
	RORC	ENST00000859919.1		c.1528G>A	p.Glu510Lys	missense	Exon 11 of 11	ENSP00000529978.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000398 AC: 1 AN: 251358 AF XY: 0.00000736

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000889 AC: 13 AN: 1461822 Hom.: 0 Cov.: 31 AF XY: 0.0000138 AC XY: 10 AN XY: 727208

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.0000224 AC: 1 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86244

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.00000899 AC: 10 AN: 1111972

Other (OTH) AF: 0.00 AC: 0 AN: 60392

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000843 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.11	D
BayesDel_noAF	Uncertain	0.010
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.065	T
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.27
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.28	T
MetaSVM	Uncertain	0.43	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		1.1
PrimateAI	Uncertain	0.50	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.38
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.051	T
Polyphen		0.98	D
Vest4		0.32
MutPred		0.25		Gain of ubiquitination at E511 (P = 0.0051)
MVP		0.50
MPC		0.78
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.24
gMVP		0.30
Mutation Taster		=85/15	polymorphism

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: rs1469359718; hg19: chr1-151779974; COSMIC: COSV100562045; COSMIC: COSV100562045;