Genetic Variant NM_001417890.1:c.1933G>A (chrX-119589774-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_001417890.1(NKRF):c.1930G>A(p.Glu644Lys) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 22)

Consequence

NKRF
NM_001417890.1 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.53

Publications

0 publications found

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]

NKRF links:

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]

UBE2A Gene-Disease associations (from GenCC):

syndromic X-linked intellectual disability Nascimento type
Inheritance: XL Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, G2P, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)

UBE2A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.828

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001417890.1. 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
	NKRF	NM_001417890.1	MANE Select	c.1930G>A	p.Glu644Lys	missense	Exon 4 of 4	NP_001404819.1	A0AAG2UWQ9
	NKRF	NR_163972.1		n.2459G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NKRF	ENST00000304449.8	TSL:1	c.1651G>A	p.Glu551Lys	missense	Exon 3 of 3	ENSP00000304803.5	O15226-1
NKRF	ENST00000688521.1		c.1930G>A	p.Glu644Lys	missense	Exon 4 of 4	ENSP00000508667.1	A0A8I5KX72
NKRF	ENST00000542113.3	TSL:3	c.1696G>A	p.Glu566Lys	missense	Exon 4 of 4	ENSP00000442308.1	O15226-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Pathogenic

0.36

BayesDel_noAF

Pathogenic

0.28

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.48

FATHMM_MKL

Uncertain

0.96

LIST_S2

Pathogenic

0.97

M_CAP

Pathogenic

0.68

MetaRNN

Pathogenic

0.83

MetaSVM

Uncertain

-0.23

MutationAssessor

Pathogenic

3.2

PhyloP100

7.5

PrimateAI

Uncertain

0.71

PROVEAN

Uncertain

-2.7

REVEL

Uncertain

0.46

Sift

Uncertain

0.0090

Sift4G

Uncertain

0.017

Polyphen

0.97

Vest4

0.78

MutPred

0.56

Gain of MoRF binding (P = 0.0065)

MVP

0.88

MPC

2.0

ClinPred

0.98

GERP RS

6.0

Varity_R

0.83

gMVP

0.94

Mutation Taster

=57/43

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over