NM_001145263.2:c.1524C>G

Variant names:

• chr10-46010397-G-C
• rs79761167
• NM_001145263.2:c.1524C>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001145263.2(NCOA4):​c.1524C>G​(p.Pro508Pro) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00206 in 1,614,112 control chromosomes in the GnomAD database, including 25 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0020 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (22 hom.)
• Consequence: NCOA4 NM_001145263.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.928
• Publications: 5 publications found

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 10-46010397-G-C is Benign according to our data. Variant chr10-46010397-G-C is described in ClinVar as Benign. ClinVar VariationId is 715258.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.928 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00198 (301/152232) while in subpopulation EAS AF = 0.0189 (98/5186). AF 95% confidence interval is 0.0159. There are 3 homozygotes in GnomAd4. There are 150 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001145263.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA4	NM_001145263.2	MANE Select	c.1524C>G	p.Pro508Pro	synonymous	Exon 8 of 10	NP_001138735.1	Q13772-1
	NCOA4	NM_001145260.2		c.1572C>G	p.Pro524Pro	synonymous	Exon 9 of 12	NP_001138732.1	Q13772-4
	NCOA4	NM_001145261.2		c.1572C>G	p.Pro524Pro	synonymous	Exon 9 of 11	NP_001138733.1	Q13772-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA4	ENST00000581486.6	TSL:1 MANE Select	c.1524C>G	p.Pro508Pro	synonymous	Exon 8 of 10	ENSP00000462943.1	Q13772-1
	NCOA4	ENST00000578454.5	TSL:1	c.1572C>G	p.Pro524Pro	synonymous	Exon 9 of 12	ENSP00000463027.1	Q13772-4
	NCOA4	ENST00000585132.5	TSL:1	c.1524C>G	p.Pro508Pro	synonymous	Exon 8 of 10	ENSP00000464054.1	Q13772-1

Frequencies

GnomAD3 genomes AF: 0.00199 AC: 302 AN: 152114 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000435

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0190

Gnomad SAS AF: 0.00808

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00110

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00421 AC: 1056 AN: 251064 AF XY: 0.00381

Gnomad AFR exome AF: 0.000187

Gnomad AMR exome AF: 0.0118

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000757

Gnomad OTH exome AF: 0.00360

GnomAD4 exome AF: 0.00207 AC: 3019 AN: 1461880 Hom.: 22 Cov.: 32 AF XY: 0.00215 AC XY: 1564 AN XY: 727238

African (AFR) AF: 0.000269 AC: 9 AN: 33480

American (AMR) AF: 0.0108 AC: 485 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.0135 AC: 534 AN: 39700

South Asian (SAS) AF: 0.00635 AC: 548 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5764

European-Non Finnish (NFE) AF: 0.00109 AC: 1207 AN: 1112008

Other (OTH) AF: 0.00384 AC: 232 AN: 60394

GnomAD4 genome AF: 0.00198 AC: 301 AN: 152232 Hom.: 3 Cov.: 32 AF XY: 0.00202 AC XY: 150 AN XY: 74424

African (AFR) AF: 0.000433 AC: 18 AN: 41530

American (AMR) AF: 0.00445 AC: 68 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5186

South Asian (SAS) AF: 0.00809 AC: 39 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10604

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00110 AC: 75 AN: 68000

Other (OTH) AF: 0.00142 AC: 3 AN: 2116

Alfa AF: 0.000874 Hom.: 0

Bravo AF: 0.00268

Asia WGS AF: 0.0200 AC: 68 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	4.2
DANN	Benign	0.58
PhyloP100		0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

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

Other links and lift over

dbSNP: rs79761167; hg19: chr10-51585425;