Genetic Variant NKX3-1:p.Val4Phe (chr8-23682880-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_006167.4(NKX3-1):c.10G>T(p.Val4Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000767 in 1,304,326 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 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. V4I) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 7.7e-7 ( 0 hom. )

Consequence

NKX3-1
NM_006167.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.930

Publications

0 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:

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ACMG classification

Classification was made for transcript

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=0.11136329).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKX3-1	NM_006167.4 link	c.10G>T	p.Val4Phe	missense_variant	Exon 1 of 2	ENST00000380871.5	NP_006158.2	Q99801-1
NKX3-1	NM_001256339.1 link	c.10G>T	p.Val4Phe	missense_variant	Exon 1 of 3		NP_001243268.1	Q99801-3
NKX3-1	NR_046072.2 link	n.35+24G>T		intron_variant	Intron 1 of 1
LOC107986930	XR_001745842.2 link	n.1312+14130C>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.10G>T	p.Val4Phe	missense_variant	Exon 1 of 2	1	NM_006167.4	ENSP00000370253.4		Q99801-1
NKX3-1	ENST00000523261.1 link	c.10G>T	p.Val4Phe	missense_variant	Exon 1 of 3	1		ENSP00000429729.1		Q99801-3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

7.67e-7

AC:

AN:

1304326

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

639604

show subpopulations

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

African (AFR)

AF:

0.00

AC:

AN:

26184

American (AMR)

AF:

0.00

AC:

AN:

25886

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21366

East Asian (EAS)

AF:

0.00

AC:

AN:

29538

South Asian (SAS)

AF:

0.0000145

AC:

AN:

68996

European-Finnish (FIN)

AF:

0.00

AC:

AN:

32064

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4006

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1042092

Other (OTH)

AF:

0.00

AC:

AN:

54194

⚠️ 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.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.375

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.039

BayesDel_noAF

Benign

-0.29

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.13

T;.

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.15

LIST_S2

Benign

0.41

T;T

M_CAP

Uncertain

0.18

MetaRNN

Benign

0.11

T;T

MetaSVM

Benign

-0.50

MutationAssessor

Benign

1.0

L;L

PhyloP100

-0.93

PrimateAI

Uncertain

0.69

PROVEAN

Benign

-0.93

N;N

REVEL

Benign

0.22

Sift

Uncertain

0.025

D;D

Sift4G

Uncertain

0.031

D;T

Polyphen

0.21

B;.

Vest4

0.15

MutPred

0.063

Gain of glycosylation at P5 (P = 0.2124);Gain of glycosylation at P5 (P = 0.2124);

MVP

0.86

MPC

0.28

ClinPred

0.11

GERP RS

-1.4

PromoterAI

0.38

Neutral

(source)

Varity_R

0.077

gMVP

0.23

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over