NM_001145263.2:c.1484C>T

Variant names:

• chr10-46010437-G-A
• rs142672975
• NM_001145263.2:c.1484C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001145263.2(NCOA4):​c.1484C>T​(p.Ser495Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00227 in 1,614,176 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0023 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (23 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.32
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.014239132).
• BP6: Variant 10-46010437-G-A is Benign according to our data. Variant chr10-46010437-G-A is described in ClinVar as Benign. ClinVar VariationId is 715257.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 = 0.00226 (344/152298) while in subpopulation EAS AF = 0.0189 (98/5184). AF 95% confidence interval is 0.0159. There are 3 homozygotes in GnomAd4. There are 166 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.1484C>T	p.Ser495Leu	missense	Exon 8 of 10	NP_001138735.1	Q13772-1
	NCOA4	NM_001145260.2		c.1532C>T	p.Ser511Leu	missense	Exon 9 of 12	NP_001138732.1	Q13772-4
	NCOA4	NM_001145261.2		c.1532C>T	p.Ser511Leu	missense	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.1484C>T	p.Ser495Leu	missense	Exon 8 of 10	ENSP00000462943.1	Q13772-1
	NCOA4	ENST00000578454.5	TSL:1	c.1532C>T	p.Ser511Leu	missense	Exon 9 of 12	ENSP00000463027.1	Q13772-4
	NCOA4	ENST00000585132.5	TSL:1	c.1484C>T	p.Ser495Leu	missense	Exon 8 of 10	ENSP00000464054.1	Q13772-1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152182 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00471

Gnomad ASJ AF: 0.00662

Gnomad EAS AF: 0.0191

Gnomad SAS AF: 0.00827

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00451 AC: 1132 AN: 251246 AF XY: 0.00415

Gnomad AFR exome AF: 0.000309

Gnomad AMR exome AF: 0.0115

Gnomad ASJ exome AF: 0.00516

Gnomad EAS exome AF: 0.0186

Gnomad FIN exome AF: 0.0000462

Gnomad NFE exome AF: 0.00102

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00227 AC: 3319 AN: 1461878 Hom.: 23 Cov.: 32 AF XY: 0.00234 AC XY: 1705 AN XY: 727236

African (AFR) AF: 0.000329 AC: 11 AN: 33480

American (AMR) AF: 0.0107 AC: 477 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00551 AC: 144 AN: 26136

East Asian (EAS) AF: 0.0134 AC: 532 AN: 39700

South Asian (SAS) AF: 0.00639 AC: 551 AN: 86252

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53418

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.00120 AC: 1337 AN: 1112004

Other (OTH) AF: 0.00429 AC: 259 AN: 60396

GnomAD4 genome AF: 0.00226 AC: 344 AN: 152298 Hom.: 3 Cov.: 32 AF XY: 0.00223 AC XY: 166 AN XY: 74470

African (AFR) AF: 0.000505 AC: 21 AN: 41564

American (AMR) AF: 0.00471 AC: 72 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00662 AC: 23 AN: 3472

East Asian (EAS) AF: 0.0189 AC: 98 AN: 5184

South Asian (SAS) AF: 0.00828 AC: 40 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00125 AC: 85 AN: 68010

Other (OTH) AF: 0.00236 AC: 5 AN: 2116

Alfa AF: 0.00163 Hom.: 0

Bravo AF: 0.00286

Asia WGS AF: 0.0210 AC: 73 AN: 3478

ClinVar

ClinVar submissions

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
AlphaMissense	Benign	0.087
BayesDel_noAF	Pathogenic	0.54
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.014	T
PhyloP100		5.3
Sift4G	Uncertain	0.0030	D
Vest4		0.38
gMVP		0.71

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

Other links and lift over

dbSNP: rs142672975; hg19: chr10-51585385;