rs1804645

Variant names:

• chr2-24752089-C-T
• rs1804645
• NM_003743.5:c.3814C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BS1 BS2

The NM_003743.5(NCOA1):​c.3814C>T​(p.Pro1272Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0217 in 1,614,086 control chromosomes in the GnomAD database, including 452 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P1272L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.016 (29 hom., cov: 32)
  • Exomes 𝑓: 0.022 (423 hom.)
• Consequence: NCOA1 NM_003743.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.88
• Publications: 27 publications found

Genes affected

NCOA1 (HGNC:7668): (nuclear receptor coactivator 1) The protein encoded by this gene acts as a transcriptional coactivator for steroid and nuclear hormone receptors. It is a member of the p160/steroid receptor coactivator (SRC) family and like other family members has histone acetyltransferase activity and contains a nuclear localization signal, as well as bHLH and PAS domains. The product of this gene binds nuclear receptors directly and stimulates the transcriptional activities in a hormone-dependent fashion. Alternatively spliced transcript variants encoding different isoforms have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0031810105).
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.016 (2430/152292) while in subpopulation NFE AF = 0.0259 (1760/68014). AF 95% confidence interval is 0.0249. There are 29 homozygotes in GnomAd4. There are 1121 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2430 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003743.5. 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
	NCOA1	NM_003743.5	MANE Select	c.3814C>T	p.Pro1272Ser	missense	Exon 20 of 23	NP_003734.3
	NCOA1	NM_147233.2		c.3814C>T	p.Pro1272Ser	missense	Exon 18 of 21	NP_671766.1	Q15788-3
	NCOA1	NM_001362950.1		c.3814C>T	p.Pro1272Ser	missense	Exon 20 of 24	NP_001349879.1	Q15788-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NCOA1	ENST00000348332.8	TSL:1 MANE Select	c.3814C>T	p.Pro1272Ser	missense	Exon 20 of 23	ENSP00000320940.5	Q15788-1
	NCOA1	ENST00000395856.3	TSL:1	c.3814C>T	p.Pro1272Ser	missense	Exon 18 of 21	ENSP00000379197.3	Q15788-3
	NCOA1	ENST00000288599.9	TSL:1	c.3814C>T	p.Pro1272Ser	missense	Exon 18 of 22	ENSP00000288599.5	Q15788-2

Frequencies

GnomAD3 genomes AF: 0.0160 AC: 2431 AN: 152174 Hom.: 29 Cov.: 32

Gnomad AFR AF: 0.00487

Gnomad AMI AF: 0.0296

Gnomad AMR AF: 0.0166

Gnomad ASJ AF: 0.0115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00932

Gnomad FIN AF: 0.00556

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.0259

Gnomad OTH AF: 0.0181

GnomAD2 exomes AF: 0.0169 AC: 4245 AN: 251356 AF XY: 0.0177

Gnomad AFR exome AF: 0.00357

Gnomad AMR exome AF: 0.0136

Gnomad ASJ exome AF: 0.0129

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00582

Gnomad NFE exome AF: 0.0262

Gnomad OTH exome AF: 0.0176

GnomAD4 exome AF: 0.0223 AC: 32665 AN: 1461794 Hom.: 423 Cov.: 33 AF XY: 0.0223 AC XY: 16244 AN XY: 727188

African (AFR) AF: 0.00376 AC: 126 AN: 33478

American (AMR) AF: 0.0145 AC: 649 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 297 AN: 26136

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39698

South Asian (SAS) AF: 0.0123 AC: 1058 AN: 86254

European-Finnish (FIN) AF: 0.00681 AC: 364 AN: 53416

Middle Eastern (MID) AF: 0.0149 AC: 86 AN: 5768

European-Non Finnish (NFE) AF: 0.0259 AC: 28842 AN: 1111932

Other (OTH) AF: 0.0206 AC: 1242 AN: 60392

GnomAD4 genome AF: 0.0160 AC: 2430 AN: 152292 Hom.: 29 Cov.: 32 AF XY: 0.0151 AC XY: 1121 AN XY: 74474

African (AFR) AF: 0.00486 AC: 202 AN: 41570

American (AMR) AF: 0.0166 AC: 254 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0115 AC: 40 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00912 AC: 44 AN: 4826

European-Finnish (FIN) AF: 0.00556 AC: 59 AN: 10618

Middle Eastern (MID) AF: 0.0238 AC: 7 AN: 294

European-Non Finnish (NFE) AF: 0.0259 AC: 1760 AN: 68014

Other (OTH) AF: 0.0175 AC: 37 AN: 2116

Alfa AF: 0.0227 Hom.: 169

Bravo AF: 0.0170

TwinsUK AF: 0.0245 AC: 91

ALSPAC AF: 0.0298 AC: 115

ESP6500AA AF: 0.00704 AC: 31

ESP6500EA AF: 0.0293 AC: 252

ExAC AF: 0.0168 AC: 2045

Asia WGS AF: 0.00491 AC: 18 AN: 3478

EpiCase AF: 0.0276

EpiControl AF: 0.0288

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.58	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.029
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.93	D
MetaRNN	Benign	0.0032	T
MetaSVM	Benign	-0.76	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.9
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.11
Sift	Uncertain	0.014	D
Sift4G	Benign	0.49	T
Polyphen		0.19	B
Vest4		0.16
MPC		0.28
ClinPred		0.013	T
GERP RS		5.1
Varity_R		0.12
gMVP		0.20
Mutation Taster		=98/2	polymorphism (auto)

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: rs1804645; hg19: chr2-24974958; COSMIC: COSV56044297;