rs142141845

chr1-151816709-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_005060.4(RORC):c.253C>T(p.His85Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000283 in 1,606,054 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00028 (1 hom.)
• Consequence: RORC NM_005060.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.34341308).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RORC	NM_005060.4	c.253C>T	p.His85Tyr	missense_variant	4/11	ENST00000318247.7
RORC	NM_001001523.2	c.190C>T	p.His64Tyr	missense_variant	3/10
RORC	XM_006711484.5	c.415C>T	p.His139Tyr	missense_variant	5/12
RORC	XM_047427201.1	c.190C>T	p.His64Tyr	missense_variant	3/6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RORC	ENST00000318247.7	c.253C>T	p.His85Tyr	missense_variant	4/11	1	NM_005060.4	P4

Frequencies

GnomAD3 genomes AF: 0.000282 AC: 43 AN: 152246 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000169

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000309

Gnomad OTH AF: 0.000956

GnomAD3 exomes AF: 0.000310 AC: 73 AN: 235356 Hom.: 0 AF XY: 0.000362 AC XY: 46 AN XY: 127042

Gnomad AFR exome AF: 0.0000675

Gnomad AMR exome AF: 0.000426

Gnomad ASJ exome AF: 0.000417

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000696

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000282

Gnomad OTH exome AF: 0.000697

GnomAD4 exome AF: 0.000283 AC: 412 AN: 1453690 Hom.: 1 Cov.: 31 AF XY: 0.000323 AC XY: 233 AN XY: 722232

Gnomad4 AFR exome AF: 0.000210

Gnomad4 AMR exome AF: 0.000436

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000673

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000231

Gnomad4 OTH exome AF: 0.000599

GnomAD4 genome AF: 0.000282 AC: 43 AN: 152364 Hom.: 0 Cov.: 33 AF XY: 0.000268 AC XY: 20 AN XY: 74510

Gnomad4 AFR AF: 0.000168

Gnomad4 AMR AF: 0.000653

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000309

Gnomad4 OTH AF: 0.000946

Alfa AF: 0.000385 Hom.: 0

Bravo AF: 0.000321

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000349 AC: 3

ExAC AF: 0.000255 AC: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 17, 2022

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 85 of the RORC protein (p.His85Tyr). This variant is present in population databases (rs142141845, gnomAD 0.07%). This variant has not been reported in the literature in individuals affected with RORC-related conditions. ClinVar contains an entry for this variant (Variation ID: 583219). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.040	T
BayesDel_noAF	Pathogenic	0.19
Cadd	Pathogenic	28
Dann	Uncertain	1.0
Eigen	Uncertain	0.35
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D;D
M_CAP	Pathogenic	0.33	D
MetaRNN	Benign	0.34	T;T
MetaSVM	Uncertain	0.59	D
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.89	D
PROVEAN	Uncertain	-3.4	D;D
REVEL	Pathogenic	0.65
Sift	Benign	0.060	T;T
Sift4G	Benign	0.11	T;T
Polyphen		0.93	.;P
Vest4		0.73
MVP		0.50
MPC		1.4
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.36
gMVP		0.76

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

LitVar

Other links and lift over

dbSNP: rs142141845; hg19: chr1-151789185;