X-119590463-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001417890.1(NKRF):​c.1241G>T​(p.Gly414Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000165 in 1,209,701 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. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000090 ( 0 hom., 0 hem., cov: 22)
Exomes 𝑓: 9.1e-7 ( 0 hom. 0 hem. )

Consequence

NKRF
NM_001417890.1 missense

Scores

1
16

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.91
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 Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.09892446).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKRFNM_001417890.1 linkc.1241G>T p.Gly414Val missense_variant Exon 4 of 4 NP_001404819.1
NKRFNR_163972.1 linkn.1770G>T 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.1241G>T p.Gly414Val missense_variant Exon 4 of 4 ENSP00000508667.1 A0A8I5KX72

Frequencies

GnomAD3 genomes
AF:
0.00000896
AC:
1
AN:
111617
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33807
show subpopulations
Gnomad AFR
AF:
0.0000326
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:
0.00
Gnomad OTH
AF:
0.00
GnomAD4 exome
AF:
9.11e-7
AC:
1
AN:
1098084
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
363444
show subpopulations
Gnomad4 AFR exome
AF:
0.0000379
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.00000896
AC:
1
AN:
111617
Hom.:
0
Cov.:
22
AF XY:
0.00
AC XY:
0
AN XY:
33807
show subpopulations
Gnomad4 AFR
AF:
0.0000326
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:
0.00
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
May 14, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1007G>T (p.G336V) alteration is located in exon 4 (coding exon 3) of the NKRF gene. This alteration results from a G to T substitution at nucleotide position 1007, causing the glycine (G) at amino acid position 336 to be replaced by a valine (V). 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
0.15
BayesDel_addAF
Benign
-0.37
T
BayesDel_noAF
Benign
-0.77
CADD
Benign
9.7
DANN
Benign
0.79
DEOGEN2
Benign
0.20
T;T;.
FATHMM_MKL
Benign
0.66
D
LIST_S2
Benign
0.67
.;T;T
M_CAP
Benign
0.0055
T
MetaRNN
Benign
0.099
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.0
N;N;.
PrimateAI
Uncertain
0.49
T
PROVEAN
Benign
-0.36
N;N;N
REVEL
Benign
0.017
Sift
Benign
0.091
T;T;T
Sift4G
Benign
0.29
T;T;T
Polyphen
0.15
B;B;.
Vest4
0.11
MutPred
0.40
Gain of sheet (P = 0.0125);Gain of sheet (P = 0.0125);.;
MVP
0.22
MPC
1.0
ClinPred
0.15
T
GERP RS
3.7
Varity_R
0.080
gMVP
0.33

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: rs1208523052; hg19: chrX-118724426; API