Genetic Variant NKAP:p.Asp111His (chrX-119943275-C-G) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_024528.4(NKAP):c.331G>C(p.Asp111His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000405 in 1,208,424 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 10 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000080 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000036 ( 0 hom. 9 hem. )

Consequence

NKAP
NM_024528.4 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 0.846

Publications

1 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: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.04308498).

BP6

Variant X-119943275-C-G is Benign according to our data. Variant chrX-119943275-C-G is described in ClinVar as Likely_benign. ClinVar VariationId is 2593078.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Hemizygotes in GnomAdExome4 at 9 XL gene

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.331G>C	p.Asp111His	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.331G>C	p.Asp111His	missense	Exon 1 of 9	ENSP00000360464.3	Q8N5F7
RHOXF1P3	ENST00000640298.3	TSL:5	c.-1502C>G		5_prime_UTR	Exon 1 of 5	ENSP00000515421.1	A0A994J3T1
NKAP	ENST00000652253.1		c.328G>C	p.Asp110His	missense	Exon 1 of 9	ENSP00000498376.1	A0A494C050

Frequencies

GnomAD3 genomes

AF:

0.0000800

AC:

AN:

112463

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00302

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:

0.000107

AC:

AN:

178017

AF XY:

0.0000624

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000111

Gnomad ASJ exome

AF:

0.00210

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000227

GnomAD4 exome

AF:

0.0000365

AC:

AN:

1095961

Hom.:

Cov.:

AF XY:

0.0000249

AC XY:

AN XY:

361645

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26368

American (AMR)

AF:

0.000114

AC:

AN:

35024

Ashkenazi Jewish (ASJ)

AF:

0.00140

AC:

AN:

19270

East Asian (EAS)

AF:

0.00

AC:

AN:

30178

South Asian (SAS)

AF:

0.00

AC:

AN:

53843

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40358

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3954

European-Non Finnish (NFE)

AF:

0.00000238

AC:

AN:

841004

Other (OTH)

AF:

0.000152

AC:

AN:

45962

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.498

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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

AF:

0.0000800

AC:

AN:

112463

Hom.:

Cov.:

AF XY:

0.0000289

AC XY:

AN XY:

34637

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31019

American (AMR)

AF:

0.00

AC:

AN:

10732

Ashkenazi Jewish (ASJ)

AF:

0.00302

AC:

AN:

2647

East Asian (EAS)

AF:

0.00

AC:

AN:

3537

South Asian (SAS)

AF:

0.00

AC:

AN:

2722

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6175

Middle Eastern (MID)

AF:

0.00

AC:

AN:

237

European-Non Finnish (NFE)

AF:

0.0000188

AC:

AN:

53192

Other (OTH)

AF:

0.00

AC:

AN:

1523

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.519

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:

0.0000868

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000577

AC:

ClinVar

ClinVar submissions

Significance:Likely benign

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

0.27

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.013

FATHMM_MKL

Benign

0.50

LIST_S2

Benign

0.68

M_CAP

Benign

0.037

MetaRNN

Benign

0.043

MetaSVM

Benign

-0.97

MutationAssessor

Uncertain

2.1

PhyloP100

0.85

PrimateAI

Uncertain

0.54

PROVEAN

Benign

-0.98

REVEL

Benign

0.092

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.012

Polyphen

1.0

Vest4

0.22

MutPred

0.21

Gain of MoRF binding (P = 0.0781)

MVP

0.48

MPC

1.3

ClinPred

0.22

GERP RS

3.2

PromoterAI

-0.088

Neutral

(source)

Varity_R

0.23

gMVP

0.48

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over