10-46010581-T-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001145263.2(NCOA4):c.1340A>G(p.Lys447Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00461 in 1,614,224 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

• Frequency:
  • Genomes: 𝑓 0.0035 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0047 (27 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: not provided no classification provided O:1
• Conservation: PhyloP100: 1.40

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011272341).
• BS2: High Homozygotes in GnomAd at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA4	NM_001145263.2	c.1340A>G	p.Lys447Arg	missense_variant	8/10	ENST00000581486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA4	ENST00000581486.6	c.1340A>G	p.Lys447Arg	missense_variant	8/10	1	NM_001145263.2	P2

Frequencies

GnomAD3 genomes AF: 0.00354 AC: 539 AN: 152220 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00116

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00451

Gnomad ASJ AF: 0.0181

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00500

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00368 AC: 925 AN: 251236 Hom.: 5 AF XY: 0.00375 AC XY: 509 AN XY: 135862

Gnomad AFR exome AF: 0.000743

Gnomad AMR exome AF: 0.00199

Gnomad ASJ exome AF: 0.0198

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000915

Gnomad FIN exome AF: 0.000416

Gnomad NFE exome AF: 0.00516

Gnomad OTH exome AF: 0.00327

GnomAD4 exome AF: 0.00473 AC: 6909 AN: 1461886 Hom.: 27 Cov.: 32 AF XY: 0.00465 AC XY: 3383 AN XY: 727242

Gnomad4 AFR exome AF: 0.000508

Gnomad4 AMR exome AF: 0.00195

Gnomad4 ASJ exome AF: 0.0179

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000823

Gnomad4 FIN exome AF: 0.00101

Gnomad4 NFE exome AF: 0.00535

Gnomad4 OTH exome AF: 0.00435

GnomAD4 genome AF: 0.00354 AC: 539 AN: 152338 Hom.: 2 Cov.: 32 AF XY: 0.00346 AC XY: 258 AN XY: 74500

Gnomad4 AFR AF: 0.00115

Gnomad4 AMR AF: 0.00451

Gnomad4 ASJ AF: 0.0181

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00500

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00502 Hom.: 1

Bravo AF: 0.00365

ClinVar

Significance: not provided

Submissions summary: Other:1

Revision: no classification provided

Submissions by phenotype

not provided Other:1

not provided, no classification provided

phenotyping only

GenomeConnect, ClinGen

-

Variant interpretted as Uncertain significance and reported on 10/30/2014 by GTR ID 320384. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.080
BayesDel_noAF	Benign	-0.75
Cadd	Benign	20
Dann	Uncertain	0.98
DEOGEN2	Benign	0.16	T;T;T;T;.;.;.
MetaRNN	Benign	0.011	T;T;T;T;T;T;T
Sift4G	Benign	0.12	T;T;T;T;T;T;T
Vest4		0.080
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.10

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs61754798; hg19: chr10-51585241;