rs2241666

Positions:

• chr10-56358869-T-A
• chr10-56358869-T-C

Variant summary

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

The NM_007057.4(ZWINT):​c.559A>T​(p.Arg187Trp) 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. 15/21 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. R187G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: ZWINT NM_007057.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.159

Genes affected

ZWINT (HGNC:13195): (ZW10 interacting kinetochore protein) This gene encodes a protein that is clearly involved in kinetochore function although an exact role is not known. It interacts with ZW10, another kinetochore protein, possibly regulating the association between ZW10 and kinetochores. The encoded protein localizes to prophase kinetochores before ZW10 does and it remains detectable on the kinetochore until late anaphase. It has a uniform distribution in the cytoplasm of interphase cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2008]

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=0.13371897).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ZWINT	NM_007057.4	c.559A>T	p.Arg187Trp	missense_variant	6/9	ENST00000373944.8	NP_008988.2
ZWINT	NM_032997.3	c.559A>T	p.Arg187Trp	missense_variant	6/8		NP_127490.1
ZWINT	NM_001005413.1	c.519+40A>T		intron_variant			NP_001005413.1
ZWINT	XR_428692.4	n.596A>T		non_coding_transcript_exon_variant	6/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ZWINT	ENST00000373944.8	c.559A>T	p.Arg187Trp	missense_variant	6/9	1	NM_007057.4	ENSP00000363055	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 74

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.51
CADD	Benign	16
DANN	Benign	0.96
DEOGEN2	Benign	0.016	T;T;.
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.043	N
LIST_S2	Benign	0.67	.;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.13	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.97	L;L;.
MutationTaster	Benign	1.0	P;P;P;P;P
PrimateAI	Benign	0.19	T
PROVEAN	Uncertain	-3.8	D;D;D
REVEL	Benign	0.050
Sift	Uncertain	0.029	D;D;D
Sift4G	Uncertain	0.021	D;D;D
Polyphen		0.97	D;D;.
Vest4		0.32
MutPred		0.35		Loss of disorder (P = 0.0081);Loss of disorder (P = 0.0081);.;
MVP		0.24
MPC		0.098
ClinPred		0.50	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.029

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs2241666; hg19: chr10-58118630;