X-119589972-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001417890.1(NKRF):​c.1732G>C​(p.Glu578Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 22)

Consequence

NKRF
NM_001417890.1 missense

Scores

2
9
6

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.53
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.756

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
NKRFNM_001417890.1 linkc.1732G>C p.Glu578Gln missense_variant Exon 4 of 4 NP_001404819.1
NKRFNR_163972.1 linkn.2261G>C 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.1732G>C p.Glu578Gln missense_variant Exon 4 of 4 ENSP00000508667.1 A0A8I5KX72

Frequencies

GnomAD3 genomes
Cov.:
22
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
22

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Oct 01, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1498G>C (p.E500Q) alteration is located in exon 4 (coding exon 3) of the NKRF gene. This alteration results from a G to C substitution at nucleotide position 1498, causing the glutamic acid (E) at amino acid position 500 to be replaced by a glutamine (Q). 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
Uncertain
0.46
BayesDel_addAF
Uncertain
0.034
T
BayesDel_noAF
Benign
-0.19
CADD
Uncertain
25
DANN
Uncertain
0.99
DEOGEN2
Benign
0.29
T;T;.
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Benign
0.84
.;T;T
M_CAP
Pathogenic
0.66
D
MetaRNN
Pathogenic
0.76
D;D;D
MetaSVM
Uncertain
-0.26
T
MutationAssessor
Benign
1.1
L;L;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.2
N;N;N
REVEL
Uncertain
0.39
Sift
Uncertain
0.025
D;D;D
Sift4G
Uncertain
0.053
T;T;T
Polyphen
0.93
P;P;.
Vest4
0.54
MutPred
0.50
Gain of sheet (P = 0.0221);Gain of sheet (P = 0.0221);.;
MVP
0.76
MPC
1.9
ClinPred
0.82
D
GERP RS
5.6
Varity_R
0.51
gMVP
0.91

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

No publications associated with this variant yet.

Other links and lift over

hg19: chrX-118723935; API