Genetic Variant NCOA4:p.Asp223Asp (chr10-46012928-G-A) – ACMG Classification: Benign (-11 pts)

Variant summary

Our verdict is Benign. The variant received -11 ACMG points: 0P and 11B. BP4_ModerateBP7BA1

The NM_001145263.2(NCOA4):c.669C>T(p.Asp223Asp) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.103 in 1,613,784 control chromosomes in the GnomAD database, including 8,808 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.091 ( 644 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8164 hom. )

Consequence

NCOA4
NM_001145263.2 synonymous

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.655

Publications

18 publications found

Variant links:

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]

NCOA4 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -11 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.4).

BP7

Synonymous conserved (PhyloP=0.655 with no splicing effect.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.108 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA4	NM_001145263.2 link	c.669C>T	p.Asp223Asp	synonymous_variant	Exon 7 of 10	ENST00000581486.6	NP_001138735.1	Q13772-1A0A024QZI5B2R5V0Q96E88

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA4	ENST00000581486.6 link	c.669C>T	p.Asp223Asp	synonymous_variant	Exon 7 of 10	1	NM_001145263.2	ENSP00000462943.1		Q13772-1

Frequencies

GnomAD3 genomes

AF:

0.0910

AC:

13841

AN:

152108

Hom.:

645

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0656

Gnomad AMI

AF:

0.151

Gnomad AMR

AF:

0.0839

Gnomad ASJ

AF:

0.0805

Gnomad EAS

AF:

0.0633

Gnomad SAS

AF:

0.0687

Gnomad FIN

AF:

0.0965

Gnomad MID

AF:

0.0924

Gnomad NFE

AF:

0.110

Gnomad OTH

AF:

0.0942

GnomAD2 exomes

AF:

0.0898

AC:

22560

AN:

251302

AF XY:

0.0902

show subpopulations

Gnomad AFR exome

AF:

0.0650

Gnomad AMR exome

AF:

0.0591

Gnomad ASJ exome

AF:

0.0884

Gnomad EAS exome

AF:

0.0484

Gnomad FIN exome

AF:

0.0997

Gnomad NFE exome

AF:

0.111

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.104

AC:

151898

AN:

1461558

Hom.:

8164

Cov.:

AF XY:

0.103

AC XY:

74687

AN XY:

727080

show subpopulations

African (AFR)

AF:

0.0650

AC:

2175

AN:

33474

American (AMR)

AF:

0.0614

AC:

2746

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.0896

AC:

2342

AN:

26132

East Asian (EAS)

AF:

0.101

AC:

4003

AN:

39698

South Asian (SAS)

AF:

0.0730

AC:

6298

AN:

86246

European-Finnish (FIN)

AF:

0.101

AC:

5411

AN:

53408

Middle Eastern (MID)

AF:

0.0710

AC:

409

AN:

5762

European-Non Finnish (NFE)

AF:

0.110

AC:

122566

AN:

1111752

Other (OTH)

AF:

0.0985

AC:

5948

AN:

60376

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

Heterozygous variant carriers

7013

14027

21040

28054

35067

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4390

8780

13170

17560

21950

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0909

AC:

13838

AN:

152226

Hom.:

644

Cov.:

AF XY:

0.0895

AC XY:

6660

AN XY:

74430

show subpopulations

African (AFR)

AF:

0.0656

AC:

2724

AN:

41550

American (AMR)

AF:

0.0837

AC:

1280

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0805

AC:

279

AN:

3464

East Asian (EAS)

AF:

0.0633

AC:

328

AN:

5182

South Asian (SAS)

AF:

0.0684

AC:

330

AN:

4826

European-Finnish (FIN)

AF:

0.0965

AC:

1023

AN:

10600

Middle Eastern (MID)

AF:

0.0925

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.110

AC:

7513

AN:

68002

Other (OTH)

AF:

0.0927

AC:

196

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

636

1273

1909

2546

3182

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

158

316

474

632

790

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0987

Hom.:

677

Bravo

AF:

0.0884

Asia WGS

AF:

0.0670

AC:

237

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.40

CADD

Benign

1.6

(source)

DANN

Benign

0.58

PhyloP100

0.66

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over