8-23682817-G-A

Position:

• chr8-23682817-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006167.4(NKX3-1):​c.73C>T​(p.Pro25Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,384,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: NKX3-1 NM_006167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.47

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36440146).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NKX3-1	NM_006167.4	c.73C>T	p.Pro25Ser	missense_variant	1/2	ENST00000380871.5
LOC107986930	XR_001745842.2	n.1312+14067G>A		intron_variant, non_coding_transcript_variant
NKX3-1	NM_001256339.1	c.33+40C>T		intron_variant
NKX3-1	NR_046072.2	n.35+87C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NKX3-1	ENST00000380871.5	c.73C>T	p.Pro25Ser	missense_variant	1/2	1	NM_006167.4	P2
NKX3-1	ENST00000523261.1	c.33+40C>T		intron_variant		1		A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.0000188 AC: 26 AN: 1384304 Hom.: 0 Cov.: 31 AF XY: 0.0000146 AC XY: 10 AN XY: 685514

Gnomad4 AFR exome AF: 0.000103

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000203

Gnomad4 OTH exome AF: 0.0000173

GnomAD4 genome Cov.: 33

Bravo AF: 0.0000113

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

Apr 07, 2022

The c.73C>T (p.P25S) alteration is located in exon 1 (coding exon 1) of the NKX3-1 gene. This alteration results from a C to T substitution at nucleotide position 73, causing the proline (P) at amino acid position 25 to be replaced by a serine (S). 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	0.30
BayesDel_addAF	Uncertain	0.035	T
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T
Eigen	Benign	0.033
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Benign	0.63	T
M_CAP	Pathogenic	0.68	D
MetaRNN	Benign	0.36	T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	1.0	D;N
PrimateAI	Pathogenic	0.83	D
PROVEAN	Benign	-1.5	N
REVEL	Benign	0.29
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.036	D
Polyphen		0.91	P
Vest4		0.11
MutPred		0.10		Gain of phosphorylation at P25 (P = 0.0408);
MVP		0.94
MPC		0.65
ClinPred		0.59	D
GERP RS		3.4
Varity_R		0.14
gMVP		0.75

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

Other links and lift over

dbSNP: rs962693280; hg19: chr8-23540330;