chr20-47625452-A-G

Position:

• chr20-47625452-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_181659.3(NCOA3):​c.328A>G​(p.Lys110Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCOA3 NM_181659.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.49

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.38642177).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NCOA3	NM_181659.3	c.328A>G	p.Lys110Glu	missense_variant	5/23	ENST00000371998.8	NP_858045.1
NCOA3	NM_001174087.2	c.328A>G	p.Lys110Glu	missense_variant	5/23		NP_001167558.1
NCOA3	NM_006534.4	c.328A>G	p.Lys110Glu	missense_variant	5/23		NP_006525.2
NCOA3	NM_001174088.2	c.328A>G	p.Lys110Glu	missense_variant	5/23		NP_001167559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NCOA3	ENST00000371998.8	c.328A>G	p.Lys110Glu	missense_variant	5/23	1	NM_181659.3	ENSP00000361066	P4
NCOA3	ENST00000372004.7	c.328A>G	p.Lys110Glu	missense_variant	5/23	1		ENSP00000361073	A2
NCOA3	ENST00000371997.3	c.328A>G	p.Lys110Glu	missense_variant	5/23	1		ENSP00000361065	A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

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

Nov 21, 2023

The c.328A>G (p.K110E) alteration is located in exon 5 (coding exon 3) of the NCOA3 gene. This alteration results from a A to G substitution at nucleotide position 328, causing the lysine (K) at amino acid position 110 to be replaced by a glutamic acid (E). 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	Pathogenic	0.96
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.52	.;D;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.75
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	0.99	D;D;D
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.39	T;T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.50
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.48
MutPred		0.40		Loss of ubiquitination at K110 (P = 0.0077);Loss of ubiquitination at K110 (P = 0.0077);Loss of ubiquitination at K110 (P = 0.0077);
MVP		0.78
MPC		0.32
ClinPred		0.99	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.78
gMVP		0.53

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-46254196;