rs41263732

Positions:

• chr1-151814975-C-T

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_005060.4(RORC):​c.749G>A​(p.Ser250Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00445 in 1,614,210 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0036 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0045 (21 hom.)
• Consequence: RORC NM_005060.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.329

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.006422162).
• BP6: Variant 1-151814975-C-T is Benign according to our data. Variant chr1-151814975-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 475713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-151814975-C-T is described in Lovd as [Likely_benign].
• BS2: High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RORC	NM_005060.4	c.749G>A	p.Ser250Asn	missense_variant	5/11	ENST00000318247.7	NP_005051.2
RORC	NM_001001523.2	c.686G>A	p.Ser229Asn	missense_variant	4/10		NP_001001523.1
RORC	XM_006711484.5	c.911G>A	p.Ser304Asn	missense_variant	6/12		XP_006711547.3
RORC	XM_047427201.1	c.686G>A	p.Ser229Asn	missense_variant	4/6		XP_047283157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RORC	ENST00000318247.7	c.749G>A	p.Ser250Asn	missense_variant	5/11	1	NM_005060.4	ENSP00000327025	P4

Frequencies

GnomAD3 genomes AF: 0.00363 AC: 552 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000820

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00772

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000470

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00556

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00347 AC: 871 AN: 251302 Hom.: 4 AF XY: 0.00362 AC XY: 492 AN XY: 135820

Gnomad AFR exome AF: 0.000862

Gnomad AMR exome AF: 0.00474

Gnomad ASJ exome AF: 0.00139

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000817

Gnomad FIN exome AF: 0.000878

Gnomad NFE exome AF: 0.00523

Gnomad OTH exome AF: 0.00669

GnomAD4 exome AF: 0.00454 AC: 6634 AN: 1461874 Hom.: 21 Cov.: 32 AF XY: 0.00444 AC XY: 3231 AN XY: 727238

Gnomad4 AFR exome AF: 0.00111

Gnomad4 AMR exome AF: 0.00499

Gnomad4 ASJ exome AF: 0.00103

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000684

Gnomad4 FIN exome AF: 0.000861

Gnomad4 NFE exome AF: 0.00539

Gnomad4 OTH exome AF: 0.00351

GnomAD4 genome AF: 0.00362 AC: 552 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.00353 AC XY: 263 AN XY: 74492

Gnomad4 AFR AF: 0.000818

Gnomad4 AMR AF: 0.00771

Gnomad4 ASJ AF: 0.000865

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00103

Gnomad4 FIN AF: 0.000470

Gnomad4 NFE AF: 0.00556

Gnomad4 OTH AF: 0.00425

Alfa AF: 0.00526 Hom.: 3

Bravo AF: 0.00375

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00493 AC: 19

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00477 AC: 41

ExAC AF: 0.00350 AC: 425

EpiCase AF: 0.00513

EpiControl AF: 0.00599

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 26, 2024

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Dec 01, 2023

RORC: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_addAF	Benign	-0.41	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	16
DANN	Benign	0.92
DEOGEN2	Benign	0.046	.;T
Eigen	Benign	-0.61
Eigen_PC	Benign	-0.57
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.59	T;T
M_CAP	Benign	0.035	D
MetaRNN	Benign	0.0064	T;T
MetaSVM	Benign	-0.62	T
MutationAssessor	Benign	0.40	.;N
MutationTaster	Benign	0.99	N;N;N
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-0.55	N;N
REVEL	Benign	0.18
Sift	Benign	0.32	T;T
Sift4G	Benign	0.56	T;T
Polyphen		0.0	.;B
Vest4		0.11
MVP		0.068
MPC		0.50
ClinPred		0.0050	T
GERP RS		-0.19
Varity_R		0.050
gMVP		0.30

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs41263732; hg19: chr1-151787451; COSMIC: COSV100562237; COSMIC: COSV100562237;