chr10-46010599-C-T

Variant names:

• chr10-46010599-C-T
• rs146205784
• NM_001145263.2:c.1322G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong 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, multiple submitters, no conflicts B:2
• 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

Our verdict: Benign. The variant received -18 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_multiple_submitters_no_conflicts, 2 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 the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NCOA4	NM_001145263.2	c.1322G>A	p.Gly441Glu	missense_variant	Exon 8 of 10	ENST00000581486.6	NP_001138735.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NCOA4	ENST00000581486.6	c.1322G>A	p.Gly441Glu	missense_variant	Exon 8 of 10	1	NM_001145263.2	ENSP00000462943.1

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

GnomAD2 exomes AF: 0.00486 AC: 1220 AN: 251282 AF XY: 0.00425

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 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 AC: 331 AN: 33480

Gnomad4 AMR exome AF: 0.0112 AC: 500 AN: 44724

Gnomad4 ASJ exome AF: 0.0000765 AC: 2 AN: 26136

Gnomad4 EAS exome AF: 0.0135 AC: 534 AN: 39700

Gnomad4 SAS exome AF: 0.00636 AC: 549 AN: 86256

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53420

Gnomad4 NFE exome AF: 0.00114 AC: 1267 AN: 1112008

Gnomad4 Remaining exome AF: 0.00449 AC: 271 AN: 60392

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 AC: 0.0100409 AN: 0.0100409

Gnomad4 AMR AF: 0.00549 AC: 0.0054902 AN: 0.0054902

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.0189 AC: 0.0188825 AN: 0.0188825

Gnomad4 SAS AF: 0.00828 AC: 0.00828157 AN: 0.00828157

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.00110 AC: 0.00110275 AN: 0.00110275

Gnomad4 OTH AF: 0.00331 AC: 0.00331126 AN: 0.00331126

Alfa AF: 0.00267 Hom.: 0

Bravo AF: 0.00583

Asia WGS AF: 0.0200 AC: 69 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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;.;.;.
LIST_S2	Uncertain	0.95	.;D;D;.;D;D;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;