chrX-119943241-C-T

Variant names:

• chrX-119943241-C-T
• rs754074934
• NM_024528.4:c.365G>A

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

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
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.60

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)

ACMG classification

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
NKAP	NM_024528.4	c.365G>A	p.Arg122Lys	missense_variant	Exon 1 of 9	ENST00000371410.5	NP_078804.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKAP	ENST00000371410.5	c.365G>A	p.Arg122Lys	missense_variant	Exon 1 of 9	1	NM_024528.4	ENSP00000360464.3
RHOXF1P3	ENST00000640298.3	c.-1536C>T		5_prime_UTR_variant	Exon 1 of 5	5		ENSP00000515421.1
NKAP	ENST00000652253.1	c.362G>A	p.Arg121Lys	missense_variant	Exon 1 of 9			ENSP00000498376.1

Frequencies

GnomAD3 genomes AF: 0.0000444 AC: 5 AN: 112575 Hom.: 0 Cov.: 23 AF XY: 0.0000576 AC XY: 2 AN XY: 34723

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

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

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

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

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

Other links and lift over

dbSNP: rs754074934; hg19: chrX-119077204;