chr20-47635414-G-C

Position:

• chr20-47635414-G-C

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_181659.3(NCOA3):​c.1205G>C​(p.Ser402Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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: -0.223

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.041582644).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA3	NM_181659.3	c.1205G>C	p.Ser402Thr	missense_variant	11/23	ENST00000371998.8
NCOA3	NM_001174087.2	c.1205G>C	p.Ser402Thr	missense_variant	11/23
NCOA3	NM_006534.4	c.1205G>C	p.Ser402Thr	missense_variant	11/23
NCOA3	NM_001174088.2	c.1235G>C	p.Ser412Thr	missense_variant	11/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA3	ENST00000371998.8	c.1205G>C	p.Ser402Thr	missense_variant	11/23	1	NM_181659.3	P4
NCOA3	ENST00000372004.7	c.1205G>C	p.Ser402Thr	missense_variant	11/23	1		A2
NCOA3	ENST00000371997.3	c.1235G>C	p.Ser412Thr	missense_variant	11/23	1		A2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Jun 10, 2024

The c.1205G>C (p.S402T) alteration is located in exon 11 (coding exon 9) of the NCOA3 gene. This alteration results from a G to C substitution at nucleotide position 1205, causing the serine (S) at amino acid position 402 to be replaced by a threonine (T). 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	0.075
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.75
CADD	Benign	0.17
DANN	Benign	0.80
DEOGEN2	Benign	0.076	.;T;.
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.23	N
LIST_S2	Benign	0.65	T;T;T
M_CAP	Benign	0.0046	T
MetaRNN	Benign	0.042	T;T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L;L;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-1.1	N;N;N
REVEL	Benign	0.037
Sift	Benign	0.19	T;T;T
Sift4G	Benign	0.40	T;T;T
Polyphen		0.0020	B;B;B
Vest4		0.062
MutPred		0.21		Gain of glycosylation at S402 (P = 0.0154);Gain of glycosylation at S402 (P = 0.0154);.;
MVP		0.27
MPC		0.12
ClinPred		0.13	T
GERP RS		-3.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.041
gMVP		0.26

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: rs375357603; hg19: chr20-46264158;