X-119589972-C-G

Variant names:

• chrX-119589972-C-G
• ENST00000688521.1:c.1732G>C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

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
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.53

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]

ACMG classification

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
NKRF	NM_001417890.1	c.1732G>C	p.Glu578Gln	missense_variant	Exon 4 of 4		NP_001404819.1
NKRF	NR_163972.1	n.2261G>C		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NKRF	ENST00000688521.1	c.1732G>C	p.Glu578Gln	missense_variant	Exon 4 of 4			ENSP00000508667.1

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

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;