X-119943275-C-T

Variant names:

• chrX-119943275-C-T
• rs200925009
• ENST00000640298.3:c.-1502C>T

Variant summary

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

The NM_024528.4(NKAP):​c.331G>A​(p.Asp111Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000912 in 1,095,960 control chromosomes in the GnomAD database, with no homozygous occurrence. There are no hemizygote samples in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D111H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NKAP NM_024528.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.846
• Publications: 1 publications found

Genes affected

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

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 Gene-Disease associations (from GenCC):

• intellectual developmental disorder, X-linked, syndromic, Hackmann-Di Donato type

  Inheritance: XL Classification: STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

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=0.11314276).

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>A	p.Asp111Asn	missense	Exon 1 of 9	NP_078804.2	Q8N5F7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	RHOXF1P3	ENST00000640298.3	TSL:5	c.-1502C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 5	ENSP00000515421.1	A0A994J3T1
	NKAP	ENST00000371410.5	TSL:1 MANE Select	c.331G>A	p.Asp111Asn	missense	Exon 1 of 9	ENSP00000360464.3	Q8N5F7
	RHOXF1P3	ENST00000640298.3	TSL:5	c.-1502C>T		5_prime_UTR	Exon 1 of 5	ENSP00000515421.1	A0A994J3T1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD2 exomes AF: 0.00000562 AC: 1 AN: 178017 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000736

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 9.12e-7 AC: 1 AN: 1095960 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 361644

African (AFR) AF: 0.00 AC: 0 AN: 26368

American (AMR) AF: 0.00 AC: 0 AN: 35023

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19270

East Asian (EAS) AF: 0.0000331 AC: 1 AN: 30178

South Asian (SAS) AF: 0.00 AC: 0 AN: 53843

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40358

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3954

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 841004

Other (OTH) AF: 0.00 AC: 0 AN: 45962

GnomAD4 genome Cov.: 23

ExAC AF: 0.00000824 AC: 1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.92
CADD	Benign	16
DANN	Uncertain	0.99
DEOGEN2	Benign	0.0062	T
FATHMM_MKL	Benign	0.32	N
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.5	L
PhyloP100		0.85
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.025
Sift	Benign	0.074	T
Sift4G	Benign	0.10	T
Polyphen		0.62	P
Vest4		0.13
MutPred		0.22		Gain of MoRF binding (P = 0.0718)
MVP		0.50
MPC		1.2
ClinPred		0.43	T
GERP RS		3.2
PromoterAI		-0.025	Neutral
Varity_R		0.12
gMVP		0.38
Mutation Taster		=96/4	polymorphism

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

Other links and lift over

dbSNP: rs200925009; hg19: chrX-119077238; COSMIC: COSV101004297;