10-46012911-G-A

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001145263.2(NCOA4):c.686C>T(p.Thr229Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0074 in 1,614,104 control chromosomes in the GnomAD database, including 63 homozygotes. In-silico tool predicts a benign outcome for this variant. 7/11 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0055 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0076 (57 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0730

Genes affected

NCOA4 (HGNC:7671): (nuclear receptor coactivator 4) This gene encodes an androgen receptor coactivator. The encoded protein interacts with the androgen receptor in a ligand-dependent manner to enhance its transcriptional activity. Chromosomal translocations between this gene and the ret tyrosine kinase gene, also located on chromosome 10, have been associated with papillary thyroid carcinoma. Alternatively spliced transcript variants have been described. Pseudogenes are present on chromosomes 4, 5, 10, and 14. [provided by RefSeq, Feb 2009]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.00876838).
• BP6: Variant 10-46012911-G-A is Benign according to our data. Variant chr10-46012911-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 789307.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA4	NM_001145263.2	c.686C>T	p.Thr229Ile	missense_variant	7/10	ENST00000581486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA4	ENST00000581486.6	c.686C>T	p.Thr229Ile	missense_variant	7/10	1	NM_001145263.2	P2

Frequencies

GnomAD3 genomes AF: 0.00550 AC: 837 AN: 152192 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.00152

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.0198

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00736

Gnomad OTH AF: 0.00382

GnomAD3 exomes AF: 0.00566 AC: 1422 AN: 251246 Hom.: 7 AF XY: 0.00572 AC XY: 776 AN XY: 135768

Gnomad AFR exome AF: 0.00142

Gnomad AMR exome AF: 0.00104

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00307

Gnomad FIN exome AF: 0.0187

Gnomad NFE exome AF: 0.00738

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00760 AC: 11110 AN: 1461794 Hom.: 57 Cov.: 30 AF XY: 0.00739 AC XY: 5377 AN XY: 727212

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00136

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00362

Gnomad4 FIN exome AF: 0.0179

Gnomad4 NFE exome AF: 0.00844

Gnomad4 OTH exome AF: 0.00551

GnomAD4 genome AF: 0.00549 AC: 836 AN: 152310 Hom.: 6 Cov.: 32 AF XY: 0.00569 AC XY: 424 AN XY: 74476

Gnomad4 AFR AF: 0.00152

Gnomad4 AMR AF: 0.00170

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00331

Gnomad4 FIN AF: 0.0198

Gnomad4 NFE AF: 0.00736

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00624 Hom.: 13

Bravo AF: 0.00378

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	May 22, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	TIMM23B: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.87
Cadd	Benign	13
Dann	Benign	0.86
DEOGEN2	Benign	0.055	T;T;T;T;.;.;.
MetaRNN	Benign	0.0088	T;T;T;T;T;T;T
Sift4G	Benign	0.59	T;T;T;T;T;T;T
Vest4		0.24
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.24

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: rs113955117; hg19: chr10-51582911;