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

Variant summary

Our verdict is Benign. Variant got -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. 13/20 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 nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

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

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 made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

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

GnomAD3 exomes

AF:

0.0344

AC:

6942

AN:

202040

Hom.:

151

AF XY:

0.0355

AC XY:

4028

AN XY:

113310

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 SAS exome

AF:

0.0260

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

Gnomad4 AFR exome

AF:

0.00714

Gnomad4 AMR exome

AF:

0.0291

Gnomad4 ASJ exome

AF:

0.0472

Gnomad4 EAS exome

AF:

0.000133

Gnomad4 SAS exome

AF:

0.0261

Gnomad4 FIN exome

AF:

0.0175

Gnomad4 NFE exome

AF:

0.0480

Gnomad4 OTH exome

AF:

0.0374

GnomAD4 genome

AF:

0.0321

AC:

4888

AN:

152222

Hom.:

105

Cov.:

AF XY:

0.0305

AC XY:

2271

AN XY:

74422

show subpopulations

Gnomad4 AFR

AF:

0.00849

Gnomad4 AMR

AF:

0.0363

Gnomad4 ASJ

AF:

0.0537

Gnomad4 EAS

AF:

0.000194

Gnomad4 SAS

AF:

0.0286

Gnomad4 FIN

AF:

0.0173

Gnomad4 NFE

AF:

0.0484

Gnomad4 OTH

AF:

0.0355

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

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

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

Varity_R

0.14

gMVP

0.26

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over