10-92593376-A-G

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.1A>G(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:2
• Conservation: PhyloP100: 4.18

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 10-92593376-A-G is Pathogenic according to our data. Variant chr10-92593376-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 977833.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF11	ENST00000260731.5	c.1A>G	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:2

Revision: criteria provided, single submitter

Submissions by phenotype

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

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Génétique Moléculaire, Hôpital Robert Debré

-

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 14, 2023

This sequence change affects the initiator methionine of the KIF11 mRNA. The next in-frame methionine is located at codon 70. This variant is not present in population databases (gnomAD no frequency). Disruption of the initiator codon has been observed in individual(s) with microcephaly with or without chorioretinopathy, lymphedema, or mental retardation (PMID: 25115524, 26566857). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 977833). This variant disrupts a region of the KIF11 protein in which other variant(s) (p.Arg26Gly) have been determined to be pathogenic (Invitae). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
Cadd	Uncertain	25
Dann	Uncertain	0.99
DEOGEN2	Benign	0.19	T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.42
FATHMM_MKL	Benign	0.71	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.85	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Uncertain	-0.062	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.93	N
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.98	D
Vest4		0.95
MutPred		0.98		Loss of MoRF binding (P = 0.1152);
MVP		0.96
ClinPred		1.0	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.93
gMVP		0.66

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr10-94353133;