dbSNP rs2228013: NKX3-1:p.Arg52Cys (chr8-23682736-G-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_006167.4(NKX3-1):c.154C>T(p.Arg52Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0417 in 1,580,730 control chromosomes in the GnomAD database, including 1,467 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.032 ( 105 hom., cov: 33)

Exomes 𝑓: 0.043 ( 1362 hom. )

Consequence

NKX3-1
NM_006167.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.34

Publications

29 publications found

Variant links:

Genes affected

NKX3-1 (HGNC:7838): (NK3 homeobox 1) This gene encodes a homeobox-containing transcription factor. This transcription factor functions as a negative regulator of epithelial cell growth in prostate tissue. Aberrant expression of this gene is associated with prostate tumor progression. Alternate splicing results in multiple transcript variants of this gene. [provided by RefSeq, Jan 2012]

NKX3-1 links:

LOC107986930 (HGNC:):

LOC107986930 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

BP4

Computational evidence support a benign effect (MetaRNN=0.0021387935).

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0321 (4888/152222) while in subpopulation NFE AF = 0.0484 (3290/67996). AF 95% confidence interval is 0.047. There are 105 homozygotes in GnomAd4. There are 2271 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 105 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-1	NM_006167.4 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 2	ENST00000380871.5	NP_006158.2	Q99801-1
NKX3-1	NM_001256339.1 link	c.34-105C>T		intron_variant	Intron 1 of 2		NP_001243268.1	Q99801-3
NKX3-1	NR_046072.2 link	n.35+168C>T		intron_variant	Intron 1 of 1
LOC107986930	XR_001745842.2 link	n.1312+13986G>A		intron_variant	Intron 3 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKX3-1	ENST00000380871.5 link	c.154C>T	p.Arg52Cys	missense_variant	Exon 1 of 2	1	NM_006167.4	ENSP00000370253.4		Q99801-1
NKX3-1	ENST00000523261.1 link	c.34-105C>T		intron_variant	Intron 1 of 2	1		ENSP00000429729.1		Q99801-3

Frequencies

GnomAD3 genomes

AF:

0.0321

AC:

4890

AN:

152114

Hom.:

105

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00852

Gnomad AMI

AF:

0.107

Gnomad AMR

AF:

0.0363

Gnomad ASJ

AF:

0.0537

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0284

Gnomad FIN

AF:

0.0173

Gnomad MID

AF:

0.0350

Gnomad NFE

AF:

0.0484

Gnomad OTH

AF:

0.0359

GnomAD2 exomes

AF:

0.0344

AC:

6942

AN:

202040

AF XY:

0.0355

show subpopulations

Gnomad AFR exome

AF:

0.00951

Gnomad AMR exome

AF:

0.0279

Gnomad ASJ exome

AF:

0.0452

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0186

Gnomad NFE exome

AF:

0.0478

Gnomad OTH exome

AF:

0.0449

GnomAD4 exome

AF:

0.0428

AC:

61086

AN:

1428508

Hom.:

1362

Cov.:

AF XY:

0.0427

AC XY:

30330

AN XY:

710898

show subpopulations

African (AFR)

AF:

0.00714

AC:

219

AN:

30688

American (AMR)

AF:

0.0291

AC:

1261

AN:

43298

Ashkenazi Jewish (ASJ)

AF:

0.0472

AC:

1204

AN:

25512

East Asian (EAS)

AF:

0.000133

AC:

AN:

37612

South Asian (SAS)

AF:

0.0261

AC:

2189

AN:

83816

European-Finnish (FIN)

AF:

0.0175

AC:

669

AN:

38212

Middle Eastern (MID)

AF:

0.0502

AC:

251

AN:

5000

European-Non Finnish (NFE)

AF:

0.0480

AC:

53063

AN:

1104926

Other (OTH)

AF:

0.0374

AC:

2225

AN:

59444

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

3680

7361

11041

14722

18402

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1918

3836

5754

7672

9590

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0321

AC:

4888

AN:

152222

Hom.:

105

Cov.:

AF XY:

0.0305

AC XY:

2271

AN XY:

74422

show subpopulations

African (AFR)

AF:

0.00849

AC:

353

AN:

41554

American (AMR)

AF:

0.0363

AC:

555

AN:

15304

Ashkenazi Jewish (ASJ)

AF:

0.0537

AC:

186

AN:

3466

East Asian (EAS)

AF:

0.000194

AC:

AN:

5152

South Asian (SAS)

AF:

0.0286

AC:

138

AN:

4828

European-Finnish (FIN)

AF:

0.0173

AC:

183

AN:

10608

Middle Eastern (MID)

AF:

0.0342

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0484

AC:

3290

AN:

67996

Other (OTH)

AF:

0.0355

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

245

490

735

980

1225

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

108

162

216

270

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0391

Hom.:

Bravo

AF:

0.0330

TwinsUK

AF:

0.0483

AC:

179

ALSPAC

AF:

0.0514

AC:

198

ESP6500AA

AF:

0.00830

AC:

ESP6500EA

AF:

0.0423

AC:

337

ExAC

AF:

0.0323

AC:

3779

Asia WGS

AF:

0.0100

AC:

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Benign

-0.48

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.13

Eigen

Benign

-0.66

Eigen_PC

Benign

-0.75

FATHMM_MKL

Benign

0.22

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0021

MetaSVM

Benign

-0.50

MutationAssessor

Benign

0.69

PhyloP100

-1.3

PrimateAI

Uncertain

0.66

PROVEAN

Benign

-0.39

REVEL

Benign

0.25

Sift

Benign

0.063

Sift4G

Benign

0.063

Polyphen

0.96

Vest4

0.030

MPC

0.28

ClinPred

0.014

GERP RS

2.4

PromoterAI

0.016

Neutral

(source)

Varity_R

0.14

gMVP

0.26

Mutation Taster

=99/1

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over