chr2-121728349-C-A

Variant names:

• chr2-121728349-C-A
• rs141833997
• NM_032390.5:c.632G>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032390.5(NIFK):​c.632G>T​(p.Arg211Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R211C) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NIFK NM_032390.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.821

Genes affected

NIFK (HGNC:17838): (nucleolar protein interacting with the FHA domain of MKI67) This gene encodes a protein that interacts with the forkhead-associated domain of the Ki-67 antigen. The encoded protein may bind RNA and may play a role in mitosis and cell cycle progression. Multiple pseudogenes exist on chromosomes 5, 10, 12, 15, and 19.[provided by RefSeq, Jan 2009]

NIFK-AS1 (HGNC:27385): (NIFK antisense RNA 1)

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.060640603).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NIFK	NM_032390.5	c.632G>T	p.Arg211Leu	missense_variant	Exon 6 of 7	ENST00000285814.9	NP_115766.3
NIFK-AS1	NR_037857.1	n.1630C>A		non_coding_transcript_exon_variant	Exon 4 of 4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NIFK	ENST00000285814.9	c.632G>T	p.Arg211Leu	missense_variant	Exon 6 of 7	1	NM_032390.5	ENSP00000285814.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 27

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 03, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.632G>T (p.R211L) alteration is located in exon 6 (coding exon 6) of the NIFK gene. This alteration results from a G to T substitution at nucleotide position 632, causing the arginine (R) at amino acid position 211 to be replaced by a leucine (L). 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	0.092
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.46
CADD	Benign	0.86
DANN	Benign	0.74
DEOGEN2	Benign	0.039	T;T;T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.022	N
LIST_S2	Benign	0.38	T;T;T
M_CAP	Benign	0.0089	T
MetaRNN	Benign	0.061	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L;.;.
PrimateAI	Benign	0.25	T
PROVEAN	Benign	-1.7	N;N;N
REVEL	Benign	0.094
Sift	Benign	0.15	T;T;T
Sift4G	Benign	0.36	T;T;.
Polyphen		0.0010	B;.;.
Vest4		0.13
MutPred		0.37		Gain of catalytic residue at R211 (P = 0.0099);.;.;
MVP		0.46
MPC		0.14
ClinPred		0.083	T
GERP RS		-3.3
Varity_R		0.039
gMVP		0.15

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs141833997; hg19: chr2-122485925;