chr20-47627063-A-G

Position:

• chr20-47627063-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_181659.3(NCOA3):​c.419A>G​(p.Asn140Ser) 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 pathogenic 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: 9.32

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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.781

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA3	NM_181659.3	c.419A>G	p.Asn140Ser	missense_variant	6/23	ENST00000371998.8
NCOA3	NM_001174087.2	c.419A>G	p.Asn140Ser	missense_variant	6/23
NCOA3	NM_006534.4	c.419A>G	p.Asn140Ser	missense_variant	6/23
NCOA3	NM_001174088.2	c.419A>G	p.Asn140Ser	missense_variant	6/23

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA3	ENST00000371998.8	c.419A>G	p.Asn140Ser	missense_variant	6/23	1	NM_181659.3	P4
NCOA3	ENST00000372004.7	c.419A>G	p.Asn140Ser	missense_variant	6/23	1		A2
NCOA3	ENST00000371997.3	c.419A>G	p.Asn140Ser	missense_variant	6/23	1		A2
NCOA3	ENST00000497292.1	n.62A>G		non_coding_transcript_exon_variant	1/4	5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

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

Apr 07, 2023

The c.419A>G (p.N140S) alteration is located in exon 6 (coding exon 4) of the NCOA3 gene. This alteration results from a A to G substitution at nucleotide position 419, causing the asparagine (N) at amino acid position 140 to be replaced by a serine (S). 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	0.97
BayesDel_addAF	Benign	-0.079	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	26
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.54	.;D;.
Eigen	Pathogenic	0.75
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.97	D;D;D
M_CAP	Benign	0.028	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.3	L;L;L
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Pathogenic	-4.5	D;D;D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D;D;D
Sift4G	Benign	0.096	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.81
MVP		0.64
MPC		0.48
ClinPred		0.99	D
GERP RS		6.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.71
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr20-46255807;