10-46010599-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BS1 BS2

The NM_001145263.2(NCOA4):c.1322G>A(p.Gly441Glu) variant causes a missense change. The variant allele was found at a frequency of 0.00259 in 1,614,160 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0047 (5 hom., cov: 32)
  • Exomes 𝑓: 0.0024 (25 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.66

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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.14201319).
• BP6: Variant 10-46010599-C-T is Benign according to our data. Variant chr10-46010599-C-T is described in ClinVar as [Benign]. Clinvar id is 714454.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00473 (721/152276) while in subpopulation EAS AF= 0.0189 (98/5190). AF 95% confidence interval is 0.0159. There are 5 homozygotes in gnomad4. There are 342 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA4	NM_001145263.2	c.1322G>A	p.Gly441Glu	missense_variant	8/10	ENST00000581486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA4	ENST00000581486.6	c.1322G>A	p.Gly441Glu	missense_variant	8/10	1	NM_001145263.2	P2

Frequencies

GnomAD3 genomes AF: 0.00473 AC: 720 AN: 152158 Hom.: 5 Cov.: 32

Gnomad AFR AF: 0.0100

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00550

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00486 AC: 1220 AN: 251282 Hom.: 8 AF XY: 0.00425 AC XY: 577 AN XY: 135876

Gnomad AFR exome AF: 0.00910

Gnomad AMR exome AF: 0.0120

Gnomad ASJ exome AF: 0.0000992

Gnomad EAS exome AF: 0.0186

Gnomad SAS exome AF: 0.00634

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000844

Gnomad OTH exome AF: 0.00376

GnomAD4 exome AF: 0.00237 AC: 3466 AN: 1461884 Hom.: 25 Cov.: 32 AF XY: 0.00242 AC XY: 1762 AN XY: 727240

Gnomad4 AFR exome AF: 0.00989

Gnomad4 AMR exome AF: 0.0112

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.0135

Gnomad4 SAS exome AF: 0.00636

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00114

Gnomad4 OTH exome AF: 0.00449

GnomAD4 genome AF: 0.00473 AC: 721 AN: 152276 Hom.: 5 Cov.: 32 AF XY: 0.00459 AC XY: 342 AN XY: 74470

Gnomad4 AFR AF: 0.0100

Gnomad4 AMR AF: 0.00549

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0189

Gnomad4 SAS AF: 0.00828

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00110

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.00216 Hom.: 0

Bravo AF: 0.00583

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jun 29, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_noAF	Pathogenic	0.37
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D;D;T;D;.;.;.
MetaRNN	Benign	0.14	T;T;T;T;T;T;T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D
Vest4		0.75
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
gMVP		0.87

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs146205784; hg19: chr10-51585223;