ENST00000578454.5:c.22T>C

Variant names:

• chr10-46027444-A-G
• rs10761581
• ENST00000578454.5:c.22T>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The ENST00000578454.5(NCOA4):​c.22T>C​(p.Phe8Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000715 in 1,399,098 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 32)
  • Exomes 𝑓: 7.1e-7 (0 hom.)
• Consequence: NCOA4 ENST00000578454.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.0220
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07626161).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000578454.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA4	NM_001145263.2	MANE Select	c.-15+3082T>C		intron	N/A	NP_001138735.1
	NCOA4	NM_001145260.2		c.22T>C	p.Phe8Leu	missense	Exon 2 of 12	NP_001138732.1
	NCOA4	NM_001145261.2		c.22T>C	p.Phe8Leu	missense	Exon 2 of 11	NP_001138733.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA4	ENST00000578454.5	TSL:1	c.22T>C	p.Phe8Leu	missense	Exon 2 of 12	ENSP00000463027.1
	NCOA4	ENST00000581486.6	TSL:1 MANE Select	c.-15+3082T>C		intron	N/A	ENSP00000462943.1
	NCOA4	ENST00000579039.2	TSL:2	c.22T>C	p.Phe8Leu	missense	Exon 2 of 11	ENSP00000463455.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.15e-7 AC: 1 AN: 1399098 Hom.: 0 Cov.: 38 AF XY: 0.00 AC XY: 0 AN XY: 690074

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 31592

American (AMR) AF: 0.00 AC: 0 AN: 35698

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25174

East Asian (EAS) AF: 0.00 AC: 0 AN: 35726

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79220

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49242

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5694

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078760

Other (OTH) AF: 0.00 AC: 0 AN: 57992

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.49
BayesDel_noAF	Benign	-0.93
CADD	Benign	1.3
DANN	Benign	0.77
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.076	T
PhyloP100		0.022
Vest4		0.031
gMVP		0.45

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: rs10761581; hg19: chr10-51568378;