chrX-119589771-C-T

Variant names:

• chrX-119589771-C-T
• NM_001417890.1:c.1933G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001417890.1(NKRF):​c.1933G>A​(p.Asp645Asn) 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
• Publications: 0 publications found

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]

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)

ACMG classification

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, 0.799

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.1933G>A	p.Asp645Asn	missense	Exon 4 of 4	NP_001404819.1	A0AAG2UWQ9
	NKRF	NR_163972.1		n.2462G>A		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NKRF	ENST00000304449.8	TSL:1	c.1654G>A	p.Asp552Asn	missense	Exon 3 of 3	ENSP00000304803.5	O15226-1
	NKRF	ENST00000688521.1		c.1933G>A	p.Asp645Asn	missense	Exon 4 of 4	ENSP00000508667.1	A0A8I5KX72
	NKRF	ENST00000542113.3	TSL:3	c.1699G>A	p.Asp567Asn	missense	Exon 4 of 4	ENSP00000442308.1	O15226-2

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 22

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.66
CADD	Uncertain	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Pathogenic	0.67	D
MetaRNN	Pathogenic	0.80	D
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.41	N
PhyloP100		7.5
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-2.7	D
REVEL	Benign	0.12
Sift	Benign	0.041	D
Sift4G	Uncertain	0.018	D
Polyphen		0.74	P
Vest4		0.67
MutPred		0.34		Gain of MoRF binding (P = 0.0394)
MVP		0.55
MPC		1.6
ClinPred		0.95	D
GERP RS		6.0
Varity_R		0.57
gMVP		0.88
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

hg19: chrX-118723734;