chrX-119943241-C-T

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_024528.4(NKAP):​c.365G>A​(p.Arg122Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000142 in 1,193,913 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 59 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000044 ( 0 hom., 2 hem., cov: 23)
Exomes 𝑓: 0.00015 ( 0 hom. 57 hem. )

Consequence

NKAP
NM_024528.4 missense

Scores

2
15

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.60
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]
RHOXF1P3 (HGNC:51612): (Rhox homeobox family member 1 pseudogene 3)

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -10 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.03679326).
BP6
Variant X-119943241-C-T is Benign according to our data. Variant chrX-119943241-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3405796.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High Hemizygotes in GnomAd4 at 2 XL gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKAPNM_024528.4 linkc.365G>A p.Arg122Lys missense_variant Exon 1 of 9 ENST00000371410.5 NP_078804.2 Q8N5F7

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NKAPENST00000371410.5 linkc.365G>A p.Arg122Lys missense_variant Exon 1 of 9 1 NM_024528.4 ENSP00000360464.3 Q8N5F7
RHOXF1P3ENST00000640298.3 linkc.-1536C>T 5_prime_UTR_variant Exon 1 of 5 5 ENSP00000515421.1 A0A994J3T1
NKAPENST00000652253.1 linkc.362G>A p.Arg121Lys missense_variant Exon 1 of 9 ENSP00000498376.1 A0A494C050

Frequencies

GnomAD3 genomes
AF:
0.0000444
AC:
5
AN:
112575
Hom.:
0
Cov.:
23
AF XY:
0.0000576
AC XY:
2
AN XY:
34723
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:
0.0000939
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000360
AC:
6
AN:
166602
Hom.:
0
AF XY:
0.0000549
AC XY:
3
AN XY:
54694
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 SAS exome
AF:
0.0000640
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000669
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000153
AC:
165
AN:
1081338
Hom.:
0
Cov.:
31
AF XY:
0.000162
AC XY:
57
AN XY:
351482
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000300
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000191
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.000193
Gnomad4 OTH exome
AF:
0.0000442
GnomAD4 genome
AF:
0.0000444
AC:
5
AN:
112575
Hom.:
0
Cov.:
23
AF XY:
0.0000576
AC XY:
2
AN XY:
34723
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000939
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000434
Hom.:
0
Bravo
AF:
0.0000340
ExAC
AF:
0.0000412
AC:
5

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Benign:1
Aug 04, 2024
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.59
T
BayesDel_noAF
Benign
-0.90
CADD
Benign
17
DANN
Benign
0.94
DEOGEN2
Benign
0.0050
T
FATHMM_MKL
Benign
0.32
N
LIST_S2
Benign
0.50
T
M_CAP
Uncertain
0.087
D
MetaRNN
Benign
0.037
T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.070
N
PrimateAI
Uncertain
0.63
T
PROVEAN
Benign
-0.13
N
REVEL
Benign
0.056
Sift
Benign
1.0
T
Sift4G
Benign
0.94
T
Polyphen
0.024
B
Vest4
0.026
MVP
0.33
MPC
0.44
ClinPred
0.093
T
GERP RS
4.0
Varity_R
0.16
gMVP
0.24

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754074934; hg19: chrX-119077204; API