NM_004523.4:c.1039_1040delCT

Variant names:

• chr10-92616740-ACT-A
• rs730882061
• NM_004523.4:c.1039_1040delCT

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_1040delCT​(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:4
• 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 rank	MANE	Protein	UniProt
KIF11	NM_004523.4	c.1039_1040delCT	p.Leu347GlufsTer8	frameshift_variant	Exon 9 of 22	ENST00000260731.5	NP_004514.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF11	ENST00000260731.5	c.1039_1040delCT	p.Leu347GlufsTer8	frameshift_variant	Exon 9 of 22	1	NM_004523.4	ENSP00000260731.3

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:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Microcephaly with or without chorioretinopathy, lymphedema, or intellectual disability Pathogenic:2

Feb 10, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Nov 14, 2022

Pittsburgh Clinical Genomics Laboratory, University of Pittsburgh Medical Center

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence variant is a deletion of 2 bases (delCT) at coding nucleotides 1039-1040 of the KIF11 gene that results in a premature termition sigl that occurs 8 codons downstream of a frameshift introduced at codon 347. As this change occurs in exon 9 of 22, this variant is predicted to generate a non-functiol allele through the expression of a truncated protein or the loss of KIF11 expression due to nonsense mediated decay. This is a previously reported variant (ClinVar) that has been observed in individuals with microcephaly with or without chorioretinopathy, lymphedema or intellectual disability (PMID: 22284827, 25996076, 24281367) and familial exudative vitreoretinopathy (PMID: 31299183). This variant is absent from the gnomAD population database (0 of approximately 240,000 alleles). Studies examining the functiol consequence of this variant have not been published, to our knowledge. Given this information, we consider this a pathogenic variant. ACMG Criteria: PM2, PP5, PVS1 -

not provided Pathogenic:2

Jul 07, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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). -

Feb 01, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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) -

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;