rs863225092

Variant names:

• chr1-151811399-G-A
• rs863225092
• NM_005060.4:c.1321C>T

Your query was ambiguous. Multiple possible variants found:

• chr1-151811399-G-A
• chr1-151811399-G-C

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_005060.4(RORC):​c.1321C>T​(p.Gln441*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. 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 Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. Q441Q) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: RORC NM_005060.4 stop_gained
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 1.41
• 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 Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-151811399-G-A is Pathogenic according to our data. Variant chr1-151811399-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 217447.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORC	NM_005060.4	c.1321C>T	p.Gln441*	stop_gained	Exon 10 of 11	ENST00000318247.7	NP_005051.2
RORC	NM_001001523.2	c.1258C>T	p.Gln420*	stop_gained	Exon 9 of 10		NP_001001523.1
RORC	XM_006711484.5	c.1483C>T	p.Gln495*	stop_gained	Exon 11 of 12		XP_006711547.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORC	ENST00000318247.7	c.1321C>T	p.Gln441*	stop_gained	Exon 10 of 11	1	NM_005060.4	ENSP00000327025.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal recessive mendelian susceptibility to mycobacterial diseases due to complete RORgamma receptor deficiency Pathogenic:1

Aug 07, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	38
DANN	Uncertain	1.0
Eigen	Pathogenic	0.79
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.94	D
PhyloP100		1.4
Vest4		0.89
GERP RS		4.7
Mutation Taster		=2/198	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs863225092; hg19: chr1-151783875;