20-47627989-C-A

Variant summary

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

The NM_181659.3(NCOA3):c.789C>A(p.Asn263Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000192 in 1,613,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000018 (0 hom.)
• Consequence: NCOA3 NM_181659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.578

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=0.046130717).
• BS2: High AC in GnomAdExome at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA3	NM_181659.3	c.789C>A	p.Asn263Lys	missense_variant	8/23	ENST00000371998.8
NCOA3	NM_001174087.2	c.789C>A	p.Asn263Lys	missense_variant	8/23
NCOA3	NM_006534.4	c.789C>A	p.Asn263Lys	missense_variant	8/23
NCOA3	NM_001174088.2	c.789C>A	p.Asn263Lys	missense_variant	8/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA3	ENST00000371998.8	c.789C>A	p.Asn263Lys	missense_variant	8/23	1	NM_181659.3	P4
NCOA3	ENST00000372004.7	c.789C>A	p.Asn263Lys	missense_variant	8/23	1		A2
NCOA3	ENST00000371997.3	c.789C>A	p.Asn263Lys	missense_variant	8/23	1		A2
NCOA3	ENST00000497292.1	n.432C>A		non_coding_transcript_exon_variant	3/4	5

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152134 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000724

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

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: 0.0000716 AC: 18 AN: 251316 Hom.: 0 AF XY: 0.000103 AC XY: 14 AN XY: 135822

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000815

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000185 AC: 27 AN: 1461638 Hom.: 0 Cov.: 31 AF XY: 0.0000261 AC XY: 19 AN XY: 727152

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000353

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000199

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152252 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74434

Gnomad4 AFR AF: 0.0000722

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000741 AC: 9

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 23, 2024

The c.789C>A (p.N263K) alteration is located in exon 8 (coding exon 6) of the NCOA3 gene. This alteration results from a C to A substitution at nucleotide position 789, causing the asparagine (N) at amino acid position 263 to be replaced by a lysine (K). 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	0.27
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.62
Cadd	Benign	13
Dann	Uncertain	0.98
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.88
FATHMM_MKL	Benign	0.34	N
LIST_S2	Uncertain	0.86	D;D;D
M_CAP	Benign	0.0074	T
MetaRNN	Benign	0.046	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.8	L;L;L
MutationTaster	Benign	0.58	D;D;D;D;D
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.4	N;N;N
REVEL	Benign	0.079
Sift	Uncertain	0.029	D;D;D
Sift4G	Benign	0.44	T;T;T
Polyphen		0.026	B;B;B
Vest4		0.50
MutPred		0.39		Gain of ubiquitination at N263 (P = 0.0104);Gain of ubiquitination at N263 (P = 0.0104);Gain of ubiquitination at N263 (P = 0.0104);
MVP		0.33
MPC		0.13
ClinPred		0.050	T
GERP RS		-3.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.098
gMVP		0.45

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: rs200197392; hg19: chr20-46256733;