X-119590431-C-A

Variant names:

• chrX-119590431-C-A
• rs991277956
• NM_001417890.1:c.1273G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_001417890.1(NKRF):​c.1273G>T​(p.Ala425Ser) 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 1,097,450 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. 14/21 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. A425T) 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: 1.74
• 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: Likely_benign. The variant received -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.04266399).

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.1273G>T	p.Ala425Ser	missense	Exon 4 of 4	NP_001404819.1	A0AAG2UWQ9
	NKRF	NR_163972.1		n.1802G>T		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.994G>T	p.Ala332Ser	missense	Exon 3 of 3	ENSP00000304803.5	O15226-1
	NKRF	ENST00000688521.1		c.1273G>T	p.Ala425Ser	missense	Exon 4 of 4	ENSP00000508667.1	A0A8I5KX72
	NKRF	ENST00000542113.3	TSL:3	c.1039G>T	p.Ala347Ser	missense	Exon 4 of 4	ENSP00000442308.1	O15226-2

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 9.11e-7 AC: 1 AN: 1097450 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 362870

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: 19369

East Asian (EAS) AF: 0.00 AC: 0 AN: 30179

South Asian (SAS) AF: 0.00 AC: 0 AN: 54106

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40524

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4132

European-Non Finnish (NFE) AF: 0.00000119 AC: 1 AN: 841504

Other (OTH) AF: 0.00 AC: 0 AN: 46065

GnomAD4 genome Cov.: 23

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.77
CADD	Benign	11
DANN	Benign	0.24
DEOGEN2	Benign	0.12	T
FATHMM_MKL	Benign	0.59	D
LIST_S2	Benign	0.62	T
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.043	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.7
PrimateAI	Benign	0.33	T
PROVEAN	Benign	0.44	N
REVEL	Benign	0.044
Sift	Benign	0.99	T
Sift4G	Benign	0.85	T
Polyphen		0.0	B
Vest4		0.11
MutPred		0.26		Gain of sheet (P = 0.0149)
MVP		0.25
MPC		0.76
ClinPred		0.014	T
GERP RS		2.3
Varity_R		0.055
gMVP		0.31
Mutation Taster		=91/9	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: rs991277956; hg19: chrX-118724394;