chrX-119589444-C-T

Variant names:

• chrX-119589444-C-T
• rs2053511051
• ENST00000688521.1:c.2260G>A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_001417890.1(NKRF):​c.2260G>A​(p.Gly754Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0000228 in 1,097,956 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 8 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 21)
  • Exomes 𝑓: 0.000023 (0 hom. 8 hem.)
• Consequence: NKRF NM_001417890.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.76

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.15999332).
• BS2: High Hemizygotes in GnomAdExome4 at 8 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NKRF	NM_001417890.1	c.2260G>A	p.Gly754Ser	missense_variant	Exon 4 of 4		NP_001404819.1
NKRF	NR_163972.1	n.2789G>A		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.2260G>A	p.Gly754Ser	missense_variant	Exon 4 of 4			ENSP00000508667.1

Frequencies

GnomAD3 genomes Cov.: 21

GnomAD4 exome AF: 0.0000228 AC: 25 AN: 1097956 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 8 AN XY: 363312

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000285

Gnomad4 OTH exome AF: 0.0000217

GnomAD4 genome Cov.: 21

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 20, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2026G>A (p.G676S) alteration is located in exon 4 (coding exon 3) of the NKRF gene. This alteration results from a G to A substitution at nucleotide position 2026, causing the glycine (G) at amino acid position 676 to be replaced by a serine (S). 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	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	18
DANN	Benign	0.20
DEOGEN2	Benign	0.16	T;T;.
FATHMM_MKL	Benign	0.75	D
LIST_S2	Uncertain	0.90	.;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.16	T;T;T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	-1.1	N;N;.
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	1.4	N;N;N
REVEL	Benign	0.075
Sift	Benign	1.0	T;T;T
Sift4G	Benign	1.0	T;T;T
Polyphen		0.0030	B;B;.
Vest4		0.14
MVP		0.30
MPC		0.83
ClinPred		0.65	D
GERP RS		6.0
Varity_R		0.26
gMVP		0.63

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

LitVar

Other links and lift over

dbSNP: rs2053511051; hg19: chrX-118723407;