NM_000966.6:c.1280C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000966.6(RARG):c.1280C>T(p.Ser427Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0721 in 1,567,464 control chromosomes in the GnomAD database, including 5,112 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.073 ( 488 hom., cov: 32)

Exomes 𝑓: 0.072 ( 4624 hom. )

Consequence

RARG
NM_000966.6 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 2.49

Publications

118 publications found

Variant links:

Genes affected

RARG (HGNC:9866): (retinoic acid receptor gamma) This gene encodes a retinoic acid receptor that belongs to the nuclear hormone receptor family. Retinoic acid receptors (RARs) act as ligand-dependent transcriptional regulators. When bound to ligands, RARs activate transcription by binding as heterodimers to the retinoic acid response elements (RARE) found in the promoter regions of the target genes. In their unbound form, RARs repress transcription of their target genes. RARs are involved in various biological processes, including limb bud development, skeletal growth, and matrix homeostasis. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

RARG 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=0.0014831126).

BP6

Variant 12-53211761-G-A is Benign according to our data. Variant chr12-53211761-G-A is described in ClinVar as Benign. ClinVar VariationId is 1277170.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.175 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000966.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARG	NM_000966.6	MANE Select	c.1280C>T	p.Ser427Leu	missense	Exon 10 of 10	NP_000957.1	A8K3H3
RARG	NM_001042728.3		c.1247C>T	p.Ser416Leu	missense	Exon 8 of 8	NP_001036193.1	P13631-2
RARG	NM_001243732.2		c.1214C>T	p.Ser405Leu	missense	Exon 7 of 7	NP_001230661.1	P13631-4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
RARG	ENST00000425354.7	TSL:1 MANE Select	c.1280C>T	p.Ser427Leu	missense	Exon 10 of 10	ENSP00000388510.2	P13631-1
RARG	ENST00000338561.9	TSL:1	c.1247C>T	p.Ser416Leu	missense	Exon 8 of 8	ENSP00000343698.5	P13631-2
RARG	ENST00000394426.5	TSL:1	c.1064C>T	p.Ser355Leu	missense	Exon 9 of 9	ENSP00000377947.2	P13631-3

Frequencies

GnomAD3 genomes

AF:

0.0731

AC:

11124

AN:

152106

Hom.:

484

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0851

Gnomad AMI

AF:

0.0833

Gnomad AMR

AF:

0.0582

Gnomad ASJ

AF:

0.0588

Gnomad EAS

AF:

0.00366

Gnomad SAS

AF:

0.185

Gnomad FIN

AF:

0.0523

Gnomad MID

AF:

0.120

Gnomad NFE

AF:

0.0703

Gnomad OTH

AF:

0.0712

GnomAD2 exomes

AF:

0.0734

AC:

15716

AN:

214176

AF XY:

0.0793

show subpopulations

Gnomad AFR exome

AF:

0.0840

Gnomad AMR exome

AF:

0.0309

Gnomad ASJ exome

AF:

0.0576

Gnomad EAS exome

AF:

0.00253

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.0694

Gnomad OTH exome

AF:

0.0745

GnomAD4 exome

AF:

0.0720

AC:

101891

AN:

1415240

Hom.:

4624

Cov.:

AF XY:

0.0749

AC XY:

52520

AN XY:

701460

show subpopulations

African (AFR)

AF:

0.0799

AC:

2420

AN:

30278

American (AMR)

AF:

0.0346

AC:

1308

AN:

37750

Ashkenazi Jewish (ASJ)

AF:

0.0575

AC:

1432

AN:

24910

East Asian (EAS)

AF:

0.00151

AC:

AN:

35716

South Asian (SAS)

AF:

0.177

AC:

14186

AN:

80244

European-Finnish (FIN)

AF:

0.0557

AC:

2944

AN:

52864

Middle Eastern (MID)

AF:

0.133

AC:

747

AN:

5606

European-Non Finnish (NFE)

AF:

0.0682

AC:

74274

AN:

1089568

Other (OTH)

AF:

0.0776

AC:

4526

AN:

58304

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

4994

9988

14983

19977

24971

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

2822

5644

8466

11288

14110

<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:

0.0732

AC:

11137

AN:

152224

Hom.:

488

Cov.:

AF XY:

0.0734

AC XY:

5463

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.0849

AC:

3528

AN:

41534

American (AMR)

AF:

0.0582

AC:

890

AN:

15296

Ashkenazi Jewish (ASJ)

AF:

0.0588

AC:

204

AN:

3472

East Asian (EAS)

AF:

0.00367

AC:

AN:

5184

South Asian (SAS)

AF:

0.185

AC:

889

AN:

4814

European-Finnish (FIN)

AF:

0.0523

AC:

555

AN:

10612

Middle Eastern (MID)

AF:

0.122

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0703

AC:

4778

AN:

67990

Other (OTH)

AF:

0.0766

AC:

162

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

540

1079

1619

2158

2698

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

136

272

408

544

680

<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:

0.0692

Hom.:

1880

Bravo

AF:

0.0695

TwinsUK

AF:

0.0677

AC:

251

ALSPAC

AF:

0.0685

AC:

264

ESP6500AA

AF:

0.0887

AC:

391

ESP6500EA

AF:

0.0649

AC:

558

ExAC

AF:

0.0794

AC:

9640

Asia WGS

AF:

0.154

AC:

538

AN:

3478

ClinVar

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

Eigen

Benign

-0.035

Eigen_PC

Benign

0.032

FATHMM_MKL

Benign

0.55

LIST_S2

Uncertain

0.93

MetaRNN

Benign

0.0015

MetaSVM

Benign

-0.45

MutationAssessor

Benign

1.4

PhyloP100

2.5

PrimateAI

Benign

0.43

PROVEAN

Benign

-1.4

REVEL

Benign

0.28

Sift

Benign

0.047

Sift4G

Benign

0.14

Polyphen

0.22

Vest4

0.11

MPC

0.44

ClinPred

0.0061

GERP RS

4.5

Varity_R

0.088

gMVP

0.29

Mutation Taster

=66/34

polymorphism (auto)

(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