chr20-47627687-G-T

Position:

chr20-47627687-G-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 0P and 1B. BS2_Supporting

The NM_181659.3(NCOA3):c.659G>T(p.Arg220Ile) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,614,062 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

NCOA3
NM_181659.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.08

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 made for transcript

Verdict is Likely_benign. Variant got -1 ACMG points.

BS2

High AC in GnomAdExome4 at 6 AD gene. Variant has AC lower than other variant known as pathogenic in the gene, so the strength is limited to Supporting.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
NCOA3	NM_181659.3 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23	ENST00000371998.8	NP_858045.1
NCOA3	NM_001174087.2 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23		NP_001167558.1
NCOA3	NM_006534.4 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23		NP_006525.2
NCOA3	NM_001174088.2 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23		NP_001167559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOA3	ENST00000371998.8 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23	1	NM_181659.3	ENSP00000361066	P4	Q9Y6Q9-1
NCOA3	ENST00000372004.7 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23	1		ENSP00000361073	A2	Q9Y6Q9-5
NCOA3	ENST00000371997.3 linkuse as main transcript	c.659G>T	p.Arg220Ile	missense_variant	7/23	1		ENSP00000361065	A2	Q9Y6Q9-3
NCOA3	ENST00000497292.1 linkuse as main transcript	n.302G>T		non_coding_transcript_exon_variant	2/4	5

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000724

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000358

AC:

AN:

251260

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135778

show subpopulations

Gnomad AFR exome

AF:

0.000431

Gnomad AMR exome

AF:

0.0000289

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.00000410

AC:

AN:

1461860

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727226

show subpopulations

Gnomad4 AFR exome

AF:

0.0000896

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152202

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.0000724

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000152

Hom.:

Bravo

AF:

0.0000416

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.0000659

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 19, 2022

The c.659G>T (p.R220I) alteration is located in exon 7 (coding exon 5) of the NCOA3 gene. This alteration results from a G to T substitution at nucleotide position 659, causing the arginine (R) at amino acid position 220 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.25

BayesDel_addAF

Benign

-0.16

BayesDel_noAF

Benign

-0.16

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.53

.;D;.

Eigen

Uncertain

0.66

Eigen_PC

Uncertain

0.65

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.99

D;D;D

M_CAP

Benign

0.021

MetaRNN

Uncertain

0.49

T;T;T

MetaSVM

Benign

-1.2

MutationAssessor

Uncertain

2.1

M;M;M

MutationTaster

Benign

1.0

D;D;D;D;D

PrimateAI

Uncertain

0.57

PROVEAN

Pathogenic

-5.9

D;D;D

REVEL

Benign

0.22

Sift

Uncertain

0.0010

D;D;D

Sift4G

Uncertain

0.0030

D;D;D

Polyphen

1.0

D;D;D

Vest4

0.74

MVP

0.52

MPC

0.27

ClinPred

0.72

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.66

gMVP

0.67

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over