rs730882061

Positions:

• chr10-92616740-ACT-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_004523.4(KIF11):​c.1039_1040del​(p.Leu347GlufsTer8) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF11 NM_004523.4 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 7.76

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 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-92616740-ACT-A is Pathogenic according to our data. Variant chr10-92616740-ACT-A is described in ClinVar as [Pathogenic]. Clinvar id is 29769.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-92616740-ACT-A is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF11	NM_004523.4	c.1039_1040del	p.Leu347GlufsTer8	frameshift_variant	9/22	ENST00000260731.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF11	ENST00000260731.5	c.1039_1040del	p.Leu347GlufsTer8	frameshift_variant	9/22	1	NM_004523.4	P1

Frequencies

GnomAD3 genomes Cov.: 32

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Jul 07, 2021	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 29769). This premature translational stop signal has been observed in individual(s) with clinical features of microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability (PMID: 22284827). This variant is not present in population databases (ExAC no frequency). This sequence change creates a premature translational stop signal (p.Leu347Glufs*8) in the KIF11 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KIF11 are known to be pathogenic (PMID: 22284827, 24281367). -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 01, 2022	Frameshift variant predicted to result in protein truncation or nonsense-mediated decay in a gene for which loss-of-function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 25996076, 32730767, 22284827) -

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Feb 10, 2012

- -

Computational scores

Source: dbNSFP v4.3

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: rs730882061; hg19: chr10-94376497;