chr1-163336784-T-G

Position:

• chr1-163336784-T-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PP3_Strong PP5_Moderate

The NM_145697.3(NUF2):​c.371T>G​(p.Ile124Ser) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NUF2 NM_145697.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 4.59

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.95
• PP5: Variant 1-163336784-T-G is Pathogenic according to our data. Variant chr1-163336784-T-G is described in ClinVar as [Pathogenic]. Clinvar id is 992629.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NUF2	NM_145697.3	c.371T>G	p.Ile124Ser	missense_variant	6/14	ENST00000271452.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NUF2	ENST00000271452.8	c.371T>G	p.Ile124Ser	missense_variant	6/14	1	NM_145697.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Short stature;C4551563:Microcephaly Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Department of Molecular Cytogenetics, Toyko Medical and Dental University

Dec 22, 2020

The c.371T>G (p.Ile124Ser) variant in the NUF2 gene was identified in a Japanese individual with microcephaly and short stature. This variant occurred de novo and was predicted to be deleterious by several in silico tools. The variant is also absent from exome/genome databases including ethnically matched individuals. Functional studies revealed decreased levels of the protein and of its binding partner, NDC80. The decreased levels of both proteins led to an increase in the formation of micronuclei, abnormal spindle, aneuploidy and delayed cell growth in patient-derived lymphoblastoid cell lines. Based on the ACMG guidelines (2015), this variant meets the following criteria: PS2 (de novo with both maternity and paternity confirmed), PS3 (in vitro functional studies supportive of a damaging effect on the protein), PM2 (absent from controls) and PP3 (multiple lines of computational evidence support a deleterious effect on the gene or gene product). The combined criteria allowed the classification of the variant as pathogenic. -

not provided Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

OMIM

Jul 28, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.16
CADD	Pathogenic	29
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T;T;.;T;T;T
Eigen	Uncertain	0.64
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.91	D
LIST_S2	Uncertain	0.89	D;D;D;D;.;D
M_CAP	Benign	0.031	D
MetaRNN	Pathogenic	0.94	D;D;D;D;D;D
MetaSVM	Benign	-0.73	T
MutationAssessor	Uncertain	2.5	.;.;.;.;M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-5.3	D;D;D;D;D;D
REVEL	Uncertain	0.55
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		0.89, 0.91
MutPred		0.87		Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);Loss of stability (P = 0.0075);
MVP		0.73
MPC		1.4
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.91
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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: rs1650773164; hg19: chr1-163306574;