chrX-119589581-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001417890.1(NKRF):​c.2123G>A​(p.Arg708His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000133 in 1,203,288 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 4 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000019 ( 0 hom., 0 hem., cov: 21)
Exomes 𝑓: 0.000013 ( 0 hom. 4 hem. )

Consequence

NKRF
NM_001417890.1 missense

Scores

3
14

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.41
Variant links:
Genes affected
NKRF (HGNC:19374): (NFKB repressing factor) This gene encodes a transcriptional repressor that interacts with specific negative regulatory elements to mediate transcriptional repression of certain nuclear factor kappa B responsive genes. The protein localizes predominantly to the nucleolus with a small fraction found in the nucleoplasm and cytoplasm. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]
UBE2A (HGNC:12472): (ubiquitin conjugating enzyme E2 A) The modification of proteins with ubiquitin is an important cellular mechanism for targeting abnormal or short-lived proteins for degradation. Ubiquitination involves at least three classes of enzymes: ubiquitin-activating enzymes, ubiquitin-conjugating enzymes, and ubiquitin-protein ligases. This gene encodes a member of the E2 ubiquitin-conjugating enzyme family. This enzyme is required for post-replicative DNA damage repair, and may play a role in transcriptional regulation. Mutations in this gene are associated with cognitive disability. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2013]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.16228646).
BS2
High Hemizygotes in GnomAdExome4 at 4 gene

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKRFNM_001417890.1 linkc.2123G>A p.Arg708His missense_variant Exon 4 of 4 NP_001404819.1
NKRFNR_163972.1 linkn.2652G>A non_coding_transcript_exon_variant Exon 4 of 4

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
NKRFENST00000688521.1 linkc.2123G>A p.Arg708His missense_variant Exon 4 of 4 ENSP00000508667.1 A0A8I5KX72

Frequencies

GnomAD3 genomes
AF:
0.0000190
AC:
2
AN:
105418
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
29026
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000104
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.000300
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
3
AN:
183437
Hom.:
0
AF XY:
0.0000147
AC XY:
1
AN XY:
67881
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:
0.000105
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000122
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000128
AC:
14
AN:
1097870
Hom.:
0
Cov.:
32
AF XY:
0.0000110
AC XY:
4
AN XY:
363252
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000555
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000713
Gnomad4 OTH exome
AF:
0.000109
GnomAD4 genome
AF:
0.0000190
AC:
2
AN:
105418
Hom.:
0
Cov.:
21
AF XY:
0.00
AC XY:
0
AN XY:
29026
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.000104
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.000300
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Aug 11, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1889G>A (p.R630H) alteration is located in exon 4 (coding exon 3) of the NKRF gene. This alteration results from a G to A substitution at nucleotide position 1889, causing the arginine (R) at amino acid position 630 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Benign
-0.43
T
BayesDel_noAF
Benign
-0.65
CADD
Benign
18
DANN
Benign
0.96
DEOGEN2
Benign
0.18
T;T;.
FATHMM_MKL
Uncertain
0.78
D
LIST_S2
Uncertain
0.87
.;D;D
M_CAP
Uncertain
0.25
D
MetaRNN
Benign
0.16
T;T;T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.77
N;N;.
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-0.67
N;N;N
REVEL
Benign
0.055
Sift
Benign
0.33
T;T;T
Sift4G
Benign
0.22
T;T;T
Polyphen
0.0010
B;B;.
Vest4
0.062
MutPred
0.58
Loss of MoRF binding (P = 0.02);Loss of MoRF binding (P = 0.02);.;
MVP
0.55
MPC
1.0
ClinPred
0.10
T
GERP RS
4.9
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.076
gMVP
0.72

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: rs754192956; hg19: chrX-118723544; COSMIC: COSV58661690; API