X-119590170-C-G

Variant names:

• chrX-119590170-C-G
• rs141319437
• NM_001417890.1:c.1534G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001417890.1(NKRF):​c.1534G>C​(p.Val512Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000911 in 1,097,870 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. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V512I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 9.1e-7 (0 hom. 0 hem.)
• Consequence: NKRF NM_001417890.1 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.45
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.15711632).

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.1534G>C	p.Val512Leu	missense	Exon 4 of 4	NP_001404819.1	A0AAG2UWQ9
	NKRF	NR_163972.1		n.2063G>C		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.1255G>C	p.Val419Leu	missense	Exon 3 of 3	ENSP00000304803.5	O15226-1
	NKRF	ENST00000688521.1		c.1534G>C	p.Val512Leu	missense	Exon 4 of 4	ENSP00000508667.1	A0A8I5KX72
	NKRF	ENST00000542113.3	TSL:3	c.1300G>C	p.Val434Leu	missense	Exon 4 of 4	ENSP00000442308.1	O15226-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097870 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 363310

African (AFR) AF: 0.00 AC: 0 AN: 26394

American (AMR) AF: 0.00 AC: 0 AN: 35177

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19381

East Asian (EAS) AF: 0.00 AC: 0 AN: 30200

South Asian (SAS) AF: 0.00 AC: 0 AN: 54117

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40446

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4136

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841939

Other (OTH) AF: 0.00 AC: 0 AN: 46080

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 5

Bravo AF: 0.0000113

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	17
DANN	Uncertain	0.98
DEOGEN2	Benign	0.24	T
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.80	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.41	N
PhyloP100		1.5
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-0.68	N
REVEL	Benign	0.058
Sift	Benign	0.20	T
Sift4G	Benign	0.46	T
Polyphen		0.042	B
Vest4		0.039
MutPred		0.17		Loss of sheet (P = 0.0228)
MVP		0.38
MPC		0.82
ClinPred		0.085	T
GERP RS		5.5
Varity_R		0.15
gMVP		0.68
Mutation Taster		=97/3	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

dbSNP: rs141319437; hg19: chrX-118724133;