8-23681633-T-G

Variant names:

• chr8-23681633-T-G
• NM_006167.4:c.293A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_006167.4(NKX3-1):​c.293A>C​(p.His98Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000691 in 1,446,544 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: NKX3-1 NM_006167.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.672
• Publications: 0 publications found

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

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=0.10743064).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006167.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-1	NM_006167.4	MANE Select	c.293A>C	p.His98Pro	missense	Exon 2 of 2	NP_006158.2
	NKX3-1	NM_001256339.1		c.68A>C	p.His23Pro	missense	Exon 3 of 3	NP_001243268.1	Q99801-3
	NKX3-1	NR_046072.2		n.36-491A>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKX3-1	ENST00000380871.5	TSL:1 MANE Select	c.293A>C	p.His98Pro	missense	Exon 2 of 2	ENSP00000370253.4	Q99801-1
	NKX3-1	ENST00000523261.1	TSL:1	c.68A>C	p.His23Pro	missense	Exon 3 of 3	ENSP00000429729.1	Q99801-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.91e-7 AC: 1 AN: 1446544 Hom.: 0 Cov.: 31 AF XY: 0.00000140 AC XY: 1 AN XY: 716284

African (AFR) AF: 0.00 AC: 0 AN: 33028

American (AMR) AF: 0.00 AC: 0 AN: 43906

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25834

East Asian (EAS) AF: 0.00 AC: 0 AN: 39248

South Asian (SAS) AF: 0.00 AC: 0 AN: 85886

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 9.09e-7 AC: 1 AN: 1100112

Other (OTH) AF: 0.00 AC: 0 AN: 59592

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.081
BayesDel_addAF	Uncertain	0.020	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	19
DANN	Benign	0.96
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.72
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.28	T
M_CAP	Benign	0.071	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.30	T
MutationAssessor	Benign	1.8	L
PhyloP100		0.67
PrimateAI	Benign	0.43	T
PROVEAN	Uncertain	-2.8	D
REVEL	Benign	0.18
Sift	Benign	0.10	T
Sift4G	Benign	0.17	T
Polyphen		0.013	B
Vest4		0.084
MutPred		0.12		Gain of glycosylation at H98 (P = 0.0609)
MVP		0.90
MPC		0.64
ClinPred		0.12	T
GERP RS		3.8
Varity_R		0.44
gMVP		0.45
Mutation Taster		=92/8	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr8-23539146;