rs193922922

Positions:

• chr16-29798644-G-A
• chr16-29798644-G-T

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PM5 PP3_Strong PP5

The NM_007317.3(KIF22):​c.446G>A​(p.Arg149Gln) variant causes a missense 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R149L) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF22 NM_007317.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 6.06

Genes affected

KIF22 (HGNC:6391): (kinesin family member 22) The protein encoded by this gene is a member of the kinesin-like protein family. The family members are microtubule-dependent molecular motors that transport organelles within cells and move chromosomes during cell division. The C-terminal half of this protein has been shown to bind DNA. Studies with the Xenopus homolog suggests its essential role in metaphase chromosome alignment and maintenance. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jan 2012]

ACMG classification

Verdict is Pathogenic. Variant got 11 ACMG points.

• PM1: In a helix (size 15) in uniprot entity KIF22_HUMAN there are 8 pathogenic changes around while only 1 benign (89%) in NM_007317.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr16-29798644-G-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 30336.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.964
• PP5: Variant 16-29798644-G-A is Pathogenic according to our data. Variant chr16-29798644-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 30335.We mark this variant Likely_pathogenic, oryginal submissions are: {Pathogenic=8, Uncertain_significance=1}. Variant chr16-29798644-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF22	NM_007317.3	c.446G>A	p.Arg149Gln	missense_variant	4/14	ENST00000160827.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF22	ENST00000160827.9	c.446G>A	p.Arg149Gln	missense_variant	4/14	1	NM_007317.3	P2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 36

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:9 Uncertain:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Spondyloepimetaphyseal dysplasia with multiple dislocations Pathogenic:5 Uncertain:1

Pathogenic, criteria provided, single submitter	clinical testing	Victorian Clinical Genetics Services, Murdoch Childrens Research Institute	May 06, 2021	Based on the classification scheme VCGS_Germline_v1.3.4, this variant is classified as Pathogenic. Following criteria are met: 0105 - The mechanism of disease for this gene is not clearly established. Dominant negative is a suggested mechanism for this gene (PMID: 22152678). (I) 0107 - This gene is associated with autosomal dominant disease. (I) 0200 - Variant is predicted to result in a missense amino acid change from arginine to glutamine. (I) 0251 - This variant is heterozygous. (I) 0301 - Variant is absent from gnomAD (both v2 and v3). (SP) 0309 - An alternative amino acid change at the same position has been observed in gnomAD (v2) (14 heterozygotes, 0 homozygotes). (I) 0502 - Missense variant with conflicting in silico predictions and uninformative conservation. (I) 0602 - Variant is located in a hotspot region or cluster of pathogenic variants. Multiple pathogenic missense variants have been reported within the region this variant is found (PMID: 22152677, PMID: 22152678). (SP) 0705 - No comparable missense variants have previous evidence for pathogenicity. However, an alternative missense variant (p.Arg149Leu) with a stronger Grantham change has been reported once as de novo in an individual with spondyloepimetaphyseal dysplasia with joint laxity (SEMDJL), and was classified as pathogenic (ClinVar, OMIM, PMID: 22152678). (I) 0801 - This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been reported several times as pathogenic (ClinVar), and has been observed in many families or de novo individuals with SEMDJL (PMID: 22152677, PMID: 22152678). (SP) 1102 - Strong phenotype match for this individual. (SP) 1208 - Inheritance information for this variant is not currently available in this individual. (I) Legend: (SP) - Supporting pathogenic, (I) - Information, (SB) - Supporting benign -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 19, 2023	- -
Uncertain significance, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	Mar 25, 2024	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 09, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.R149Q in KIF22 (NM_007317.3) has been previously reported in multiple affected indviduals (Boyden ED et al; Min BJ et al). It has been submitted to the ClinVar database as Pathogenic. The p.R149Q variant is novel (not in any individuals) in gnomAD Exomes and is novel (not in any individuals) in 1000 Genomes. The p.R149Q missense variant is predicted to be damaging by both SIFT and PolyPhen2. The arginine residue at codon 149 of KIF22 is conserved in all mammalian species. The nucleotide c.446 in KIF22 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	May 14, 2024	A heterozygous missense variant in exon 4 of the KIF22 gene that results in the amino acid substitution of Glutamine for Arginine at codon 149 was detected . The observed variant has previously been reported in patients affected with Spondyloepimetaphyseal Dysplasia with Joint Laxity [PMID: 22152677] and functional studies demonstrate a damaging effect on inactivation of anaphase [PMID: 35730929]. This variant has not been reported in the 1000 genomes, gnomAD (v3.1), gnomdAD (v2.1) and topmed databases. The in silico prediction of the variant is damaging by PolyPhen-2 (HumDiv), SIFT and MutationTaster2. The reference codon is conserved across species. -

not provided Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Dec 30, 2023	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 149 of the KIF22 protein (p.Arg149Gln). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with spondyloepimetaphyseal dysplasia with joint laxity, leptodactylic type (PMID: 22152677, 22152678). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30335). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt KIF22 protein function with a negative predictive value of 80%. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on KIF22 function (PMID: 22152678). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2023	Published functional studies demonstrate a damaging effect on inactivation of anaphase (Thompson et al., 2022); Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 22152677, 22152678, 35730929) -

Inborn genetic diseases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2017

- -

See cases Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Apr 25, 2023

ACMG categories: PS3,PM1,PM2,PP3,PP5 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.23
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	30
DANN	Pathogenic	1.0
Eigen	Pathogenic	0.90
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Uncertain	0.097	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D
MetaSVM	Uncertain	0.22	D
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.6	D;D;.;D;D
Sift	Uncertain	0.0050	D;D;.;D;D
Sift4G	Uncertain	0.022	D;D;T;D;D
Polyphen		1.0	.;D;.;.;.
Vest4		0.73
MutPred		0.88		.;Gain of disorder (P = 0.1778);.;.;.;
MVP		0.92
MPC		0.91
ClinPred		0.98	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.63
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs193922922; hg19: chr16-29809965; COSMIC: COSV50717990; COSMIC: COSV50717990;