8-23681340-A-G

Position:

• chr8-23681340-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006167.4(NKX3-1):​c.586T>C​(p.Ser196Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: NKX3-1 NM_006167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.239

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]

LOC107986930 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09979528).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX3-1	NM_006167.4	c.586T>C	p.Ser196Pro	missense_variant	2/2	ENST00000380871.5
LOC107986930	XR_001745842.2	n.1312+12590A>G		intron_variant, non_coding_transcript_variant
NKX3-1	NM_001256339.1	c.361T>C	p.Ser121Pro	missense_variant	3/3
NKX3-1	NR_046072.2	n.36-198T>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX3-1	ENST00000380871.5	c.586T>C	p.Ser196Pro	missense_variant	2/2	1	NM_006167.4	P2
NKX3-1	ENST00000523261.1	c.361T>C	p.Ser121Pro	missense_variant	3/3	1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 11, 2022

The c.586T>C (p.S196P) alteration is located in exon 2 (coding exon 2) of the NKX3-1 gene. This alteration results from a T to C substitution at nucleotide position 586, causing the serine (S) at amino acid position 196 to be replaced by a proline (P). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	8.6
DANN	Benign	0.93
DEOGEN2	Benign	0.17	T;.
Eigen	Benign	-1.0
Eigen_PC	Benign	-1.0
FATHMM_MKL	Benign	0.11	N
LIST_S2	Benign	0.44	T;T
M_CAP	Benign	0.055	D
MetaRNN	Benign	0.10	T;T
MetaSVM	Benign	-0.49	T
MutationAssessor	Benign	1.2	L;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.34	T
PROVEAN	Uncertain	-2.5	D;D
REVEL	Benign	0.18
Sift	Benign	0.15	T;T
Sift4G	Benign	0.26	T;T
Polyphen		0.0020	B;.
Vest4		0.065
MutPred		0.30		Loss of phosphorylation at S196 (P = 0.0244);.;
MVP		0.89
MPC		0.26
ClinPred		0.11	T
GERP RS		-1.3
Varity_R		0.30
gMVP		0.54

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-23538853;