chr20-46062826-G-T

Variant names:

• chr20-46062826-G-T
• rs1366608550
• NM_020967.3:c.1214C>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_020967.3(NCOA5):​c.1214C>A​(p.Ser405Tyr) 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. 14/22 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: NCOA5 NM_020967.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.04
• Publications: 0 publications found

Genes affected

NCOA5 (HGNC:15909): (nuclear receptor coactivator 5) This gene encodes a coregulator for the alpha and beta estrogen receptors and the orphan nuclear receptor NR1D2. The protein localizes to the nucleus, and is thought to have both coactivator and corepressor functions. Its interaction with nuclear receptors is independent of the AF2 domain on the receptors, which is known to regulate interaction with other coreceptors. Several alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jan 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15210176).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA5	NM_020967.3	c.1214C>A	p.Ser405Tyr	missense_variant	Exon 8 of 8	ENST00000290231.11	NP_066018.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA5	ENST00000290231.11	c.1214C>A	p.Ser405Tyr	missense_variant	Exon 8 of 8	1	NM_020967.3	ENSP00000290231.6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1214C>A (p.S405Y) alteration is located in exon 8 (coding exon 7) of the NCOA5 gene. This alteration results from a C to A substitution at nucleotide position 1214, causing the serine (S) at amino acid position 405 to be replaced by a tyrosine (Y). 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	0.14
BayesDel_addAF	Benign	-0.12	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.047	T
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L
PhyloP100		2.0
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.048
Sift	Uncertain	0.014	D
Sift4G	Benign	0.078	T
Polyphen		0.73	P
Vest4		0.34
MutPred		0.26		Gain of catalytic residue at S405 (P = 0.0203);
MVP		0.25
MPC		0.82
ClinPred		0.78	D
GERP RS		5.3
Varity_R		0.12
gMVP		0.47
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1366608550; hg19: chr20-44691465;