Genetic Variant NKAP:p.Gly6Cys (chrX-119943590-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024528.4(NKAP):c.16G>T(p.Gly6Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000339 in 1,181,423 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 1 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000089 ( 0 hom., 0 hem., cov: 23)

Exomes 𝑓: 0.0000028 ( 0 hom. 1 hem. )

Consequence

NKAP
NM_024528.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.723

Publications

0 publications found

Variant links:

Genes affected

NKAP (HGNC:29873): (NFKB activating protein) This gene encodes a protein that is involved in the activation of the ubiquitous transcription factor NF-kappaB. This protein is associated with the the histone deacetylase HDAC3 and with the Notch corepressor complex, and it thereby acts as a transcriptional repressor of Notch target genes. It is also required for alphabeta T cell development. A related pseudogene has been identified on chromosome X, while a related and intronless retrocopy, which has an intact CDS and may be functional, is located on chromosome 6. [provided by RefSeq, May 2010]

NKAP links:

RHOXF1P3 (HGNC:51612): (Rhox homeobox family member 1 pseudogene 3)

RHOXF1P3 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.058112115).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_024528.4. 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
	NKAP	NM_024528.4	MANE Select	c.16G>T	p.Gly6Cys	missense	Exon 1 of 9	NP_078804.2	Q8N5F7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NKAP	ENST00000371410.5	TSL:1 MANE Select	c.16G>T	p.Gly6Cys	missense	Exon 1 of 9	ENSP00000360464.3	Q8N5F7
RHOXF1P3	ENST00000640298.3	TSL:5	c.-1187C>A		5_prime_UTR	Exon 1 of 5	ENSP00000515421.1	A0A994J3T1
NKAP	ENST00000652253.1		c.13G>T	p.Gly5Cys	missense	Exon 1 of 9	ENSP00000498376.1	A0A494C050

Frequencies

GnomAD3 genomes

AF:

0.00000891

AC:

AN:

112273

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000188

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000661

AC:

AN:

151268

AF XY:

0.0000205

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000149

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000281

AC:

AN:

1069150

Hom.:

Cov.:

AF XY:

0.00000290

AC XY:

AN XY:

344296

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

25947

American (AMR)

AF:

0.00

AC:

AN:

33129

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

17597

East Asian (EAS)

AF:

0.00

AC:

AN:

29825

South Asian (SAS)

AF:

0.00

AC:

AN:

49892

European-Finnish (FIN)

AF:

0.00

AC:

AN:

38137

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3874

European-Non Finnish (NFE)

AF:

0.00000363

AC:

AN:

825952

Other (OTH)

AF:

0.00

AC:

AN:

44797

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.00000891

AC:

AN:

112273

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

34435

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30918

American (AMR)

AF:

0.00

AC:

AN:

10702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2656

East Asian (EAS)

AF:

0.00

AC:

AN:

3539

South Asian (SAS)

AF:

0.00

AC:

AN:

2698

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6184

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53131

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.575

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.0000869

Hom.:

Bravo

AF:

0.0000227

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000153

AC:

ExAC

AF:

0.0000167

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.90

CADD

Benign

(source)

DANN

Benign

0.96

DEOGEN2

Benign

0.019

FATHMM_MKL

Benign

0.0045

LIST_S2

Benign

0.67

M_CAP

Benign

0.010

MetaRNN

Benign

0.058

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.4

PhyloP100

-0.72

PrimateAI

Uncertain

0.58

PROVEAN

Benign

-1.4

REVEL

Benign

0.013

Sift

Uncertain

0.011

Sift4G

Benign

0.070

Polyphen

0.0

Vest4

0.23

MVP

0.12

MPC

1.2

ClinPred

0.43

GERP RS

-6.2

PromoterAI

-0.021

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.21

gMVP

0.31

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over