20-47636144-G-C

Variant names:

• chr20-47636144-G-C
• rs2230782
• NM_181659.3:c.1758G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_181659.3(NCOA3):​c.1758G>C​(p.Gln586His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0812 in 1,614,100 control chromosomes in the GnomAD database, including 6,061 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.068 (451 hom., cov: 32)
  • Exomes 𝑓: 0.083 (5610 hom.)
• Consequence: NCOA3 NM_181659.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.436
• Publications: 32 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.002174139).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0954 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA3	NM_181659.3	c.1758G>C	p.Gln586His	missense_variant	Exon 12 of 23	ENST00000371998.8	NP_858045.1
NCOA3	NM_001174087.2	c.1758G>C	p.Gln586His	missense_variant	Exon 12 of 23		NP_001167558.1
NCOA3	NM_006534.4	c.1758G>C	p.Gln586His	missense_variant	Exon 12 of 23		NP_006525.2
NCOA3	NM_001174088.2	c.1788G>C	p.Gln596His	missense_variant	Exon 12 of 23		NP_001167559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA3	ENST00000371998.8	c.1758G>C	p.Gln586His	missense_variant	Exon 12 of 23	1	NM_181659.3	ENSP00000361066.3
NCOA3	ENST00000372004.7	c.1758G>C	p.Gln586His	missense_variant	Exon 12 of 23	1		ENSP00000361073.1
NCOA3	ENST00000371997.3	c.1788G>C	p.Gln596His	missense_variant	Exon 12 of 23	1		ENSP00000361065.3

Frequencies

GnomAD3 genomes AF: 0.0680 AC: 10351 AN: 152134 Hom.: 451 Cov.: 32

Gnomad AFR AF: 0.0170

Gnomad AMI AF: 0.0132

Gnomad AMR AF: 0.0699

Gnomad ASJ AF: 0.135

Gnomad EAS AF: 0.0241

Gnomad SAS AF: 0.0197

Gnomad FIN AF: 0.101

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.0973

Gnomad OTH AF: 0.0770

GnomAD2 exomes AF: 0.0707 AC: 17775 AN: 251276 AF XY: 0.0705

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.0502

Gnomad ASJ exome AF: 0.135

Gnomad EAS exome AF: 0.0245

Gnomad FIN exome AF: 0.101

Gnomad NFE exome AF: 0.0943

Gnomad OTH exome AF: 0.0796

GnomAD4 exome AF: 0.0826 AC: 120754 AN: 1461848 Hom.: 5610 Cov.: 32 AF XY: 0.0815 AC XY: 59273 AN XY: 727222

African (AFR) AF: 0.0125 AC: 417 AN: 33480

American (AMR) AF: 0.0516 AC: 2307 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.132 AC: 3444 AN: 26134

East Asian (EAS) AF: 0.0315 AC: 1251 AN: 39698

South Asian (SAS) AF: 0.0194 AC: 1675 AN: 86256

European-Finnish (FIN) AF: 0.0980 AC: 5233 AN: 53416

Middle Eastern (MID) AF: 0.0621 AC: 358 AN: 5768

European-Non Finnish (NFE) AF: 0.0912 AC: 101372 AN: 1111976

Other (OTH) AF: 0.0778 AC: 4697 AN: 60396

GnomAD4 genome AF: 0.0680 AC: 10350 AN: 152252 Hom.: 451 Cov.: 32 AF XY: 0.0675 AC XY: 5024 AN XY: 74426

African (AFR) AF: 0.0169 AC: 704 AN: 41572

American (AMR) AF: 0.0697 AC: 1066 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.135 AC: 468 AN: 3472

East Asian (EAS) AF: 0.0239 AC: 124 AN: 5178

South Asian (SAS) AF: 0.0199 AC: 96 AN: 4822

European-Finnish (FIN) AF: 0.101 AC: 1072 AN: 10590

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.0973 AC: 6620 AN: 68016

Other (OTH) AF: 0.0762 AC: 161 AN: 2112

Alfa AF: 0.0911 Hom.: 519

Bravo AF: 0.0637

TwinsUK AF: 0.0955 AC: 354

ALSPAC AF: 0.0867 AC: 334

ESP6500AA AF: 0.0222 AC: 98

ESP6500EA AF: 0.0944 AC: 812

ExAC AF: 0.0700 AC: 8500

Asia WGS AF: 0.0190 AC: 66 AN: 3478

EpiCase AF: 0.0966

EpiControl AF: 0.0956

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.70
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Benign	0.0	.;T;.
Eigen	Benign	0.068
Eigen_PC	Benign	0.095
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.88	D;D;D
MetaRNN	Benign	0.0022	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;L;.
PhyloP100		0.44
PrimateAI	Benign	0.36	T
PROVEAN	Benign	-0.60	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.42	T;T;T
Sift4G	Benign	0.12	T;T;T
Vest4		0.20
ClinPred		0.012	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.034
gMVP		0.20
Mutation Taster		=97/3	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2230782; hg19: chr20-46264888; COSMIC: COSV59067777; COSMIC: COSV59067777;