1-163326071-C-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_145697.3(NUF2):​c.20C>G​(p.Pro7Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

NUF2
NM_145697.3 missense

Scores

10
5
4

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.99
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.98

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
NUF2NM_145697.3 linkuse as main transcriptc.20C>G p.Pro7Arg missense_variant 2/14 ENST00000271452.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
NUF2ENST00000271452.8 linkuse as main transcriptc.20C>G p.Pro7Arg missense_variant 2/141 NM_145697.3 P1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000399
AC:
1
AN:
250742
Hom.:
0
AF XY:
0.00000738
AC XY:
1
AN XY:
135528
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00000882
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
29
GnomAD4 genome
Cov.:
32
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 02, 2023The c.20C>G (p.P7R) alteration is located in exon 2 (coding exon 1) of the NUF2 gene. This alteration results from a C to G substitution at nucleotide position 20, causing the proline (P) at amino acid position 7 to be replaced by an arginine (R). 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
Pathogenic
0.84
BayesDel_addAF
Pathogenic
0.38
D
BayesDel_noAF
Pathogenic
0.31
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Benign
0.27
T;T;.;T;T;T
Eigen
Pathogenic
0.79
Eigen_PC
Pathogenic
0.78
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.80
T;T;T;T;.;T
M_CAP
Benign
0.061
D
MetaRNN
Pathogenic
0.98
D;D;D;D;D;D
MetaSVM
Uncertain
0.15
D
MutationAssessor
Uncertain
2.5
.;.;.;.;M;M
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.66
T
PROVEAN
Pathogenic
-8.2
D;D;D;D;D;D
REVEL
Pathogenic
0.73
Sift
Pathogenic
0.0
D;D;D;D;D;D
Sift4G
Pathogenic
0.0
D;D;D;D;D;D
Polyphen
1.0
.;.;D;D;D;D
Vest4
0.87, 0.86
MutPred
0.93
Gain of catalytic residue at P7 (P = 0.0455);Gain of catalytic residue at P7 (P = 0.0455);Gain of catalytic residue at P7 (P = 0.0455);Gain of catalytic residue at P7 (P = 0.0455);Gain of catalytic residue at P7 (P = 0.0455);Gain of catalytic residue at P7 (P = 0.0455);
MVP
0.96
MPC
1.2
ClinPred
1.0
D
GERP RS
5.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.95
gMVP
0.93

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.20
Details are displayed if max score is > 0.2
DS_AG_spliceai
0.20
Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs754940522; hg19: chr1-163295861; API