10-92593377-T-C

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_Moderate

The NM_004523.4(KIF11):c.2T>C(p.Met1?) variant causes a start lost 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: 33)
• Consequence: KIF11 NM_004523.4 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 3.59

Genes affected

KIF11 (HGNC:6388): (kinesin family member 11) This gene encodes a motor protein that belongs to the kinesin-like protein family. Members of this protein family are known to be involved in various kinds of spindle dynamics. The function of this gene product includes chromosome positioning, centrosome separation and establishing a bipolar spindle during cell mitosis. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Pathogenic. Variant got 14 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PS1: Another start lost variant in NM_004523.4 (KIF11) was described as [Pathogenic] in ClinVar as 211271
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-92593377-T-C is Pathogenic according to our data. Variant chr10-92593377-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 488843.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr10-92593377-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF11	NM_004523.4	c.2T>C	p.Met1?	start_lost	1/22	ENST00000260731.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF11	ENST00000260731.5	c.2T>C	p.Met1?	start_lost	1/22	1	NM_004523.4	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Dec 04, 2017

The c.2 T>C pathogenic variant in the KIF11 gene has been reported previously as an apparently de novo variant in an individual with features suggestive of KIF11-related disorder (Mirzaa et al., 2014; Mirzaa et al., 2015). As this pathogenic variant changes the translation initiator Methionine codon, the resultant protein is described as p.Met1?, using a question mark to signify that it is not known if the loss of Met1 means that all protein translation is completely prevented or if an abnormal protein is produced using an alternate Methionine. The c.2 T>C variant is not observed in large population cohorts (Lek et al., 2016). We interpret c.2 T>C as a pathogenic variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Uncertain	0.060
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.49
Eigen_PC	Uncertain	0.44
FATHMM_MKL	Benign	0.65	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.93	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	0.073	D
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-1.1	N
REVEL	Uncertain	0.55
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.96
MutPred		0.98		Gain of glycosylation at M1 (P = 0.026);
MVP		0.83
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.91
gMVP		0.70

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: rs1554858130; hg19: chr10-94353134;