1-151814975-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

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. 17/22 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

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 0.329

Publications

10 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 Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

RORC links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 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 VariationId is 475713.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00362 (552/152336) while in subpopulation AMR AF = 0.00771 (118/15298). AF 95% confidence interval is 0.00658. There are 0 homozygotes in GnomAd4. There are 263 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 21 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RORC	NM_005060.4 link	c.749G>A	p.Ser250Asn	missense_variant	Exon 5 of 11	ENST00000318247.7	NP_005051.2	P51449-1Q6I9R9
RORC	NM_001001523.2 link	c.686G>A	p.Ser229Asn	missense_variant	Exon 4 of 10		NP_001001523.1	P51449-2F1D8P6
RORC	XM_006711484.5 link	c.911G>A	p.Ser304Asn	missense_variant	Exon 6 of 12		XP_006711547.3
RORC	XM_047427201.1 link	c.686G>A	p.Ser229Asn	missense_variant	Exon 4 of 6		XP_047283157.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RORC	ENST00000318247.7 link	c.749G>A	p.Ser250Asn	missense_variant	Exon 5 of 11	1	NM_005060.4	ENSP00000327025.6		P51449-1

Frequencies

GnomAD3 genomes

AF:

0.00363

AC:

552

AN:

152218

Hom.:

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.00347

AC:

871

AN:

251302

AF XY:

0.00362

show subpopulations

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 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.:

Cov.:

AF XY:

0.00444

AC XY:

3231

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00111

AC:

AN:

33480

American (AMR)

AF:

0.00499

AC:

223

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00103

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000684

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.000861

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00624

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00539

AC:

5994

AN:

1112000

Other (OTH)

AF:

0.00351

AC:

212

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.476

Heterozygous variant carriers

400

800

1199

1599

1999

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

230

460

690

920

1150

<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:

0.00362

AC:

552

AN:

152336

Hom.:

Cov.:

AF XY:

0.00353

AC XY:

263

AN XY:

74492

show subpopulations

African (AFR)

AF:

0.000818

AC:

AN:

41580

American (AMR)

AF:

0.00771

AC:

118

AN:

15298

Ashkenazi Jewish (ASJ)

AF:

0.000865

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5180

South Asian (SAS)

AF:

0.00103

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.000470

AC:

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00556

AC:

378

AN:

68024

Other (OTH)

AF:

0.00425

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

113

141

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:

0.00494

Hom.:

Bravo

AF:

0.00375

TwinsUK

AF:

0.00485

AC:

ALSPAC

AF:

0.00493

AC:

ESP6500AA

AF:

0.000681

AC:

ESP6500EA

AF:

0.00477

AC:

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

LINK: link

Submissions by phenotype

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

Benign:1

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

RORC: BP4, BS2 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.082

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.35

CADD

Benign

(source)

DANN

Benign

0.92

DEOGEN2

Benign

0.046

.;T

Eigen

Benign

-0.61

Eigen_PC

Benign

-0.57

FATHMM_MKL

Benign

0.48

LIST_S2

Benign

0.59

T;T

M_CAP

Benign

0.035

MetaRNN

Benign

0.0064

T;T

MetaSVM

Benign

-0.62

MutationAssessor

Benign

0.40

.;N

PhyloP100

0.33

PrimateAI

Benign

0.32

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

GERP RS

-0.19

Varity_R

0.050

gMVP

0.30

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over