10-46011178-T-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001145263.2(NCOA4):c.743A>G(p.Asn248Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00276 in 1,597,058 control chromosomes in the GnomAD database, including 34 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0051 (6 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (28 hom.)
• Consequence: NCOA4 NM_001145263.2 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.113

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031405091).
• BP6: Variant 10-46011178-T-C is Benign according to our data. Variant chr10-46011178-T-C is described in ClinVar as [Benign]. Clinvar id is 714453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00507 (772/152326) while in subpopulation EAS AF= 0.021 (109/5192). AF 95% confidence interval is 0.0178. There are 6 homozygotes in gnomad4. There are 370 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NCOA4	NM_001145263.2	c.743A>G	p.Asn248Ser	missense_variant	8/10	ENST00000581486.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NCOA4	ENST00000581486.6	c.743A>G	p.Asn248Ser	missense_variant	8/10	1	NM_001145263.2	P2

Frequencies

GnomAD3 genomes AF: 0.00507 AC: 772 AN: 152208 Hom.: 6 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00693

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0211

Gnomad SAS AF: 0.00849

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00125

Gnomad OTH AF: 0.00335

GnomAD3 exomes AF: 0.00522 AC: 1223 AN: 234120 Hom.: 11 AF XY: 0.00451 AC XY: 573 AN XY: 126968

Gnomad AFR exome AF: 0.00905

Gnomad AMR exome AF: 0.0125

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0218

Gnomad SAS exome AF: 0.00640

Gnomad FIN exome AF: 0.000429

Gnomad NFE exome AF: 0.00105

Gnomad OTH exome AF: 0.00450

GnomAD4 exome AF: 0.00252 AC: 3635 AN: 1444732 Hom.: 28 Cov.: 31 AF XY: 0.00257 AC XY: 1848 AN XY: 718738

Gnomad4 AFR exome AF: 0.0101

Gnomad4 AMR exome AF: 0.0113

Gnomad4 ASJ exome AF: 0.0000800

Gnomad4 EAS exome AF: 0.0148

Gnomad4 SAS exome AF: 0.00642

Gnomad4 FIN exome AF: 0.000378

Gnomad4 NFE exome AF: 0.00128

Gnomad4 OTH exome AF: 0.00484

GnomAD4 genome AF: 0.00507 AC: 772 AN: 152326 Hom.: 6 Cov.: 32 AF XY: 0.00497 AC XY: 370 AN XY: 74504

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.00692

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0210

Gnomad4 SAS AF: 0.00829

Gnomad4 FIN AF: 0.000188

Gnomad4 NFE AF: 0.00125

Gnomad4 OTH AF: 0.00332

Alfa AF: 0.00230 Hom.: 1

Bravo AF: 0.00620

Asia WGS AF: 0.0210 AC: 72 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_noAF	Benign	-0.89
Cadd	Benign	0.14
Dann	Benign	0.62
DEOGEN2	Benign	0.031	T;T;T;T;.;.;.
MetaRNN	Benign	0.0031	T;T;T;T;T;T;T
Sift4G	Benign	0.73	T;T;T;T;T;T;T
Vest4		0.025
gMVP		0.072

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs117257055; hg19: chr10-51584644;