dbSNP rs61754474: RORC:p.Tyr330Tyr (chr1-151813564-G-A) – ACMG Classification: Benign (-19 pts)

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_ModerateBP6_Very_StrongBP7BS1BS2

The NM_005060.4(RORC):c.990C>T(p.Tyr330Tyr) 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

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 0.781

Publications

4 publications found

Variant links:

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)

RORC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -19 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 Benign/Likely_benign. ClinVar VariationId is 542379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.781 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00176 (268/152272) while in subpopulation NFE AF = 0.00257 (175/68020). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 126 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 3 AR gene

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.990C>T	p.Tyr330Tyr	synonymous	Exon 7 of 11	NP_005051.2
	RORC	NM_001001523.2		c.927C>T	p.Tyr309Tyr	synonymous	Exon 6 of 10	NP_001001523.1	P51449-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RORC	ENST00000318247.7	TSL:1 MANE Select	c.990C>T	p.Tyr330Tyr	synonymous	Exon 7 of 11	ENSP00000327025.6	P51449-1
RORC	ENST00000356728.11	TSL:1	c.927C>T	p.Tyr309Tyr	synonymous	Exon 6 of 10	ENSP00000349164.6	P51449-2
RORC	ENST00000859919.1		c.990C>T	p.Tyr330Tyr	synonymous	Exon 7 of 11	ENSP00000529978.1

Frequencies

GnomAD3 genomes

AF:

0.00176

AC:

268

AN:

152154

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00189

AC:

475

AN:

251412

AF XY:

0.00185

show subpopulations

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 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.:

Cov.:

AF XY:

0.00227

AC XY:

1648

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.000418

AC:

AN:

33480

American (AMR)

AF:

0.000715

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.000306

AC:

AN:

26136

East Asian (EAS)

AF:

0.000403

AC:

AN:

39700

South Asian (SAS)

AF:

0.00106

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00288

AC:

154

AN:

53420

Middle Eastern (MID)

AF:

0.00104

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00258

AC:

2871

AN:

1111954

Other (OTH)

AF:

0.00214

AC:

129

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

179

358

536

715

894

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

282

376

470

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00176

AC:

268

AN:

152272

Hom.:

Cov.:

AF XY:

0.00169

AC XY:

126

AN XY:

74458

show subpopulations

African (AFR)

AF:

0.000626

AC:

AN:

41562

American (AMR)

AF:

0.000915

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5172

South Asian (SAS)

AF:

0.000415

AC:

AN:

4820

European-Finnish (FIN)

AF:

0.00358

AC:

AN:

10612

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00257

AC:

175

AN:

68020

Other (OTH)

AF:

0.00189

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.493

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00256

Hom.:

Bravo

AF:

0.00144

EpiCase

AF:

0.00234

EpiControl

AF:

0.00196

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (4)

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

0.18

BayesDel_noAF

Benign

-0.40

CADD

Benign

7.4

(source)

DANN

Benign

0.51

PhyloP100

0.78

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over