20-47634084-G-C

Variant names:

• chr20-47634084-G-C
• rs148666287
• NM_181659.3:c.1001G>C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_181659.3(NCOA3):​c.1001G>C​(p.Arg334Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NCOA3 NM_181659.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.88

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.905

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA3	NM_181659.3	c.1001G>C	p.Arg334Pro	missense_variant	Exon 10 of 23	ENST00000371998.8	NP_858045.1
NCOA3	NM_001174087.2	c.1001G>C	p.Arg334Pro	missense_variant	Exon 10 of 23		NP_001167558.1
NCOA3	NM_006534.4	c.1001G>C	p.Arg334Pro	missense_variant	Exon 10 of 23		NP_006525.2
NCOA3	NM_001174088.2	c.1031G>C	p.Arg344Pro	missense_variant	Exon 10 of 23		NP_001167559.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA3	ENST00000371998.8	c.1001G>C	p.Arg334Pro	missense_variant	Exon 10 of 23	1	NM_181659.3	ENSP00000361066.3
NCOA3	ENST00000372004.7	c.1001G>C	p.Arg334Pro	missense_variant	Exon 10 of 23	1		ENSP00000361073.1
NCOA3	ENST00000371997.3	c.1031G>C	p.Arg344Pro	missense_variant	Exon 10 of 23	1		ENSP00000361065.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.94
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Uncertain	0.13
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.42	.;T;.
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.91	D;D;D
MetaSVM	Benign	-0.49	T
MutationAssessor	Uncertain	2.1	M;M;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-6.1	D;D;D
REVEL	Uncertain	0.56
Sift	Uncertain	0.0010	D;D;D
Sift4G	Uncertain	0.0020	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.84
MutPred		0.75		Loss of catalytic residue at R334 (P = 0.0218);Loss of catalytic residue at R334 (P = 0.0218);.;
MVP		0.85
MPC		0.65
ClinPred		0.99	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.92
gMVP		0.97

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: rs148666287; hg19: chr20-46262828;