1-163336842-G-C

Position:

• chr1-163336842-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145697.3(NUF2):​c.429G>C​(p.Trp143Cys) 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. 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.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUF2 NM_145697.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.08

Genes affected

NUF2 (HGNC:14621): (NUF2 component of NDC80 kinetochore complex) This gene encodes a protein that is highly similar to yeast Nuf2, a component of a conserved protein complex associated with the centromere. Yeast Nuf2 disappears from the centromere during meiotic prophase when centromeres lose their connection to the spindle pole body, and plays a regulatory role in chromosome segregation. The encoded protein is found to be associated with centromeres of mitotic HeLa cells, which suggests that this protein is a functional homolog of yeast Nuf2. Alternatively spliced transcript variants that encode the same protein have been described. [provided by RefSeq, Jul 2008]

NUF2 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24299839).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUF2	NM_145697.3	c.429G>C	p.Trp143Cys	missense_variant	6/14	ENST00000271452.8	NP_663735.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUF2	ENST00000271452.8	c.429G>C	p.Trp143Cys	missense_variant	6/14	1	NM_145697.3	ENSP00000271452.3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 26

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 07, 2024

The c.429G>C (p.W143C) alteration is located in exon 6 (coding exon 5) of the NUF2 gene. This alteration results from a G to C substitution at nucleotide position 429, causing the tryptophan (W) at amino acid position 143 to be replaced by a cysteine (C). 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	0.29
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
CADD	Uncertain	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.019	T;.;T;T;T
Eigen	Benign	0.17
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Benign	0.81	T;T;T;.;T
M_CAP	Benign	0.0054	T
MetaRNN	Benign	0.24	T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.4	.;.;.;L;L
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.11	N;N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.044	D;T;T;T;T
Sift4G	Uncertain	0.032	D;T;T;T;T
Polyphen		0.86, 0.78	.;P;P;P;P
Vest4		0.56, 0.57
MutPred		0.34		Gain of catalytic residue at K146 (P = 0.0576);Gain of catalytic residue at K146 (P = 0.0576);Gain of catalytic residue at K146 (P = 0.0576);Gain of catalytic residue at K146 (P = 0.0576);Gain of catalytic residue at K146 (P = 0.0576);
MVP		0.44
MPC		1.1
ClinPred		0.83	D
GERP RS		4.7
Varity_R		0.095
gMVP		0.47

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: rs866674743; hg19: chr1-163306632;