rs2230783

Positions:

• chr20-47636715-T-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_181659.3(NCOA3):​c.2329T>G​(p.Ser777Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000457 in 1,613,830 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.0025 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00025 (2 hom.)
• Consequence: NCOA3 NM_181659.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.51

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

Verdict is Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00469175).
• BS2: High AC in GnomAd4 at 375 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA3	NM_181659.3	c.2329T>G	p.Ser777Ala	missense_variant	12/23	ENST00000371998.8
NCOA3	NM_001174087.2	c.2329T>G	p.Ser777Ala	missense_variant	12/23
NCOA3	NM_006534.4	c.2329T>G	p.Ser777Ala	missense_variant	12/23
NCOA3	NM_001174088.2	c.2359T>G	p.Ser787Ala	missense_variant	12/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA3	ENST00000371998.8	c.2329T>G	p.Ser777Ala	missense_variant	12/23	1	NM_181659.3	P4
NCOA3	ENST00000372004.7	c.2329T>G	p.Ser777Ala	missense_variant	12/23	1		A2
NCOA3	ENST00000371997.3	c.2359T>G	p.Ser787Ala	missense_variant	12/23	1		A2

Frequencies

GnomAD3 genomes AF: 0.00246 AC: 375 AN: 152132 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00847

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00118

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00191

GnomAD3 exomes AF: 0.000691 AC: 172 AN: 248834 Hom.: 1 AF XY: 0.000542 AC XY: 73 AN XY: 134676

Gnomad AFR exome AF: 0.00880

Gnomad AMR exome AF: 0.000608

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: 0.0000449

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000248 AC: 362 AN: 1461580 Hom.: 2 Cov.: 32 AF XY: 0.000212 AC XY: 154 AN XY: 727040

Gnomad4 AFR exome AF: 0.00798

Gnomad4 AMR exome AF: 0.000694

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.000414

GnomAD4 genome AF: 0.00246 AC: 375 AN: 152250 Hom.: 2 Cov.: 32 AF XY: 0.00242 AC XY: 180 AN XY: 74440

Gnomad4 AFR AF: 0.00845

Gnomad4 AMR AF: 0.00118

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00189

Alfa AF: 0.000533 Hom.: 0

Bravo AF: 0.00276

ESP6500AA AF: 0.00613 AC: 27

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000857 AC: 104

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	19
DANN	Uncertain	0.98
Eigen	Benign	0.026
Eigen_PC	Benign	0.20
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.78	T;T;T
MetaRNN	Benign	0.0047	T;T;T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.39	T
PROVEAN	Benign	-1.2	N;N;N
REVEL	Benign	0.18
Sift	Benign	0.48	T;T;T
Sift4G	Benign	0.60	T;T;T
Polyphen		0.017	B;B;P
Vest4		0.39
MVP		0.31
MPC		0.43
ClinPred		0.028	T
GERP RS		5.7
Varity_R		0.095
gMVP		0.099

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

Other links and lift over

dbSNP: rs2230783; hg19: chr20-46265459;