dbSNP rs6094752: NCOA3:p.Arg218Cys (chr20-47627680-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_181659.3(NCOA3):c.652C>T(p.Arg218Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0449 in 1,613,884 control chromosomes in the GnomAD database, including 1,914 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.051 ( 234 hom., cov: 32)

Exomes 𝑓: 0.044 ( 1680 hom. )

Consequence

NCOA3
NM_181659.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 4.41

Publications

26 publications found

Variant links:

Genes affected

NCOA3 (HGNC:7670): (nuclear receptor coactivator 3) The protein encoded by this gene is a nuclear receptor coactivator that interacts with nuclear hormone receptors to enhance their transcriptional activator functions. The encoded protein has histone acetyltransferase activity and recruits p300/CBP-associated factor and CREB binding protein as part of a multisubunit coactivation complex. This protein is initially found in the cytoplasm but is translocated into the nucleus upon phosphorylation. Several transcript variants encoding different isoforms have been found for this gene. In addition, a polymorphic repeat region is found in the C-terminus of the encoded protein. [provided by RefSeq, Mar 2010]

NCOA3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030201674).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0673 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
NCOA3	NM_181659.3 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23	ENST00000371998.8	NP_858045.1
NCOA3	NM_001174087.2 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23		NP_001167558.1
NCOA3	NM_006534.4 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23		NP_006525.2
NCOA3	NM_001174088.2 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23		NP_001167559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
NCOA3	ENST00000371998.8 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23	1	NM_181659.3	ENSP00000361066.3
NCOA3	ENST00000372004.7 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23	1		ENSP00000361073.1
NCOA3	ENST00000371997.3 link	c.652C>T	p.Arg218Cys	missense_variant	Exon 7 of 23	1		ENSP00000361065.3
NCOA3	ENST00000497292.1 link	n.295C>T		non_coding_transcript_exon_variant	Exon 2 of 4	5

Frequencies

GnomAD3 genomes

AF:

0.0514

AC:

7815

AN:

152118

Hom.:

234

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0696

Gnomad AMI

AF:

0.0932

Gnomad AMR

AF:

0.0488

Gnomad ASJ

AF:

0.0297

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.0495

Gnomad FIN

AF:

0.0351

Gnomad MID

AF:

0.0791

Gnomad NFE

AF:

0.0477

Gnomad OTH

AF:

0.0564

GnomAD2 exomes

AF:

0.0410

AC:

10311

AN:

251198

AF XY:

0.0430

show subpopulations

Gnomad AFR exome

AF:

0.0681

Gnomad AMR exome

AF:

0.0297

Gnomad ASJ exome

AF:

0.0287

Gnomad EAS exome

AF:

0.000109

Gnomad FIN exome

AF:

0.0341

Gnomad NFE exome

AF:

0.0464

Gnomad OTH exome

AF:

0.0503

GnomAD4 exome

AF:

0.0442

AC:

64585

AN:

1461650

Hom.:

1680

Cov.:

AF XY:

0.0452

AC XY:

32885

AN XY:

727134

show subpopulations

African (AFR)

AF:

0.0656

AC:

2197

AN:

33468

American (AMR)

AF:

0.0304

AC:

1360

AN:

44708

Ashkenazi Jewish (ASJ)

AF:

0.0268

AC:

699

AN:

26126

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39688

South Asian (SAS)

AF:

0.0531

AC:

4577

AN:

86232

European-Finnish (FIN)

AF:

0.0341

AC:

1820

AN:

53416

Middle Eastern (MID)

AF:

0.0983

AC:

567

AN:

5766

European-Non Finnish (NFE)

AF:

0.0455

AC:

50606

AN:

1111856

Other (OTH)

AF:

0.0457

AC:

2758

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.453

Heterozygous variant carriers

3232

6464

9696

12928

16160

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1836

3672

5508

7344

9180

<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:

0.0513

AC:

7815

AN:

152234

Hom.:

234

Cov.:

AF XY:

0.0503

AC XY:

3745

AN XY:

74442

show subpopulations

African (AFR)

AF:

0.0694

AC:

2884

AN:

41540

American (AMR)

AF:

0.0487

AC:

745

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0297

AC:

103

AN:

3470

East Asian (EAS)

AF:

0.000386

AC:

AN:

5188

South Asian (SAS)

AF:

0.0504

AC:

242

AN:

4806

European-Finnish (FIN)

AF:

0.0351

AC:

372

AN:

10598

Middle Eastern (MID)

AF:

0.0782

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0476

AC:

3241

AN:

68022

Other (OTH)

AF:

0.0558

AC:

118

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

390

779

1169

1558

1948

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0482

Hom.:

879

Bravo

AF:

0.0529

TwinsUK

AF:

0.0458

AC:

170

ALSPAC

AF:

0.0446

AC:

172

ESP6500AA

AF:

0.0658

AC:

290

ESP6500EA

AF:

0.0472

AC:

406

ExAC

AF:

0.0423

AC:

5142

Asia WGS

AF:

0.0230

AC:

AN:

3478

EpiCase

AF:

0.0530

EpiControl

AF:

0.0525

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.47

CADD

Uncertain

(source)

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.44

.;T;.

Eigen

Uncertain

0.33

Eigen_PC

Uncertain

0.47

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Benign

0.42

T;T;T

MetaRNN

Benign

0.0030

T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

M;M;M

PhyloP100

4.4

PrimateAI

Uncertain

0.57

PROVEAN

Uncertain

-3.4

D;D;D

REVEL

Benign

0.20

Sift

Benign

0.18

T;T;T

Sift4G

Uncertain

0.057

T;T;T

Polyphen

0.56

P;B;D

Vest4

0.57

MPC

0.50

ClinPred

0.045

GERP RS

6.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.36

gMVP

0.50

Mutation Taster

=88/12

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over