rs61754474

Positions:

• chr1-151813564-G-A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_005060.4(RORC):​c.990C>T​(p.Tyr330=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00222 in 1,614,098 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0018 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (3 hom.)
• Consequence: RORC NM_005060.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.781

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.4).
• BP6: Variant 1-151813564-G-A is Benign according to our data. Variant chr1-151813564-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 542379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-151813564-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=0.781 with no splicing effect.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RORC	NM_005060.4	c.990C>T	p.Tyr330=	synonymous_variant	7/11	ENST00000318247.7	NP_005051.2
RORC	XM_047427201.1	c.1009C>T	p.Arg337Cys	missense_variant	6/6		XP_047283157.1
RORC	NM_001001523.2	c.927C>T	p.Tyr309=	synonymous_variant	6/10		NP_001001523.1
RORC	XM_006711484.5	c.1152C>T	p.Tyr384=	synonymous_variant	8/12		XP_006711547.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RORC	ENST00000318247.7	c.990C>T	p.Tyr330=	synonymous_variant	7/11	1	NM_005060.4	ENSP00000327025	P4

Frequencies

GnomAD3 genomes AF: 0.00176 AC: 268 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000627

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.000917

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00358

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00257

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.00189 AC: 475 AN: 251412 Hom.: 1 AF XY: 0.00185 AC XY: 252 AN XY: 135888

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000607

Gnomad ASJ exome AF: 0.000198

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00342

Gnomad NFE exome AF: 0.00288

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00227 AC: 3321 AN: 1461826 Hom.: 3 Cov.: 31 AF XY: 0.00227 AC XY: 1648 AN XY: 727216

Gnomad4 AFR exome AF: 0.000418

Gnomad4 AMR exome AF: 0.000715

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.000403

Gnomad4 SAS exome AF: 0.00106

Gnomad4 FIN exome AF: 0.00288

Gnomad4 NFE exome AF: 0.00258

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00176 AC: 268 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.00169 AC XY: 126 AN XY: 74458

Gnomad4 AFR AF: 0.000626

Gnomad4 AMR AF: 0.000915

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.00358

Gnomad4 NFE AF: 0.00257

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.00256 Hom.: 0

Bravo AF: 0.00144

EpiCase AF: 0.00234

EpiControl AF: 0.00196

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:4

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jun 01, 2023	RORC: BP4, BP7 -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

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

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 08, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	7.4
DANN	Benign	0.51

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: rs61754474; hg19: chr1-151786040; COSMIC: COSV59095986;