NM_004523.4:c.790-1G>T

Variant names:

• chr10-92613376-G-T
• rs730882122
• NM_004523.4:c.790-1G>T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1_Moderate PM2 PP5_Very_Strong

The NM_004523.4(KIF11):​c.790-1G>T variant causes a splice acceptor, intron change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: KIF11 NM_004523.4 splice_acceptor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.84

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 12 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.07663198 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.2, offset of 13, new splice context is: attaaatgttgatcttgcAGgaa. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 10-92613376-G-T is Pathogenic according to our data. Variant chr10-92613376-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 192301.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-92613376-G-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF11	NM_004523.4	c.790-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 21	ENST00000260731.5	NP_004514.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF11	ENST00000260731.5	c.790-1G>T		splice_acceptor_variant, intron_variant	Intron 7 of 21	1	NM_004523.4	ENSP00000260731.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

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

Dec 01, 2014

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not provided Pathogenic:1

Nov 29, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects an acceptor splice site in intron 7 of the KIF11 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in KIF11 are known to be pathogenic (PMID: 22284827, 24281367). This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individuals with familial exudative vitreoretinopathy (PMID: 25124931, 27212378). ClinVar contains an entry for this variant (Variation ID: 192301). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

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

May 30, 2019

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The KIF11 c.790-1G>T variant occurs in a canonical splice site (acceptor) and is therefore predicted to disrupt or distort the normal gene product. The c.790-1G>T variant has been reported in one study, in which it is found in a heterozygous state in one individual with microcephaly and familial exudative vitreoretinopathy (Robitaille et al. 2014). The c.790-1G>T variant is not found in the Genome Aggregation Database in a region of good sequence coverage, so the variant is presumed to be rare. Similar variants, c.790-1G>A and c.790-2A>C, were identified in a presumed de novo heterozygous state in two individuals with microcephaly (Mirzaa et al. 2015; Li et al. 2016). Based on the collective evidence and application of the ACMG criteria, the c.790-1G>T variant is classified as pathogenic for microcephaly with or without chorioretinopathy, lymphedema or intellectual disability. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.36
CADD	Pathogenic	36
DANN	Uncertain	1.0
Eigen	Pathogenic	1.3
Eigen_PC	Pathogenic	1.1
FATHMM_MKL	Pathogenic	1.0	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.90		Position offset: 14
DS_AL_spliceai		0.99		Position offset: 1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs730882122; hg19: chr10-94373133;