16-29798641-C-T

Variant names:

• chr16-29798641-C-T
• rs193922921
• NM_007317.3:c.443C>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_007317.3(KIF22):​c.443C>T​(p.Pro148Leu) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P148Q) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF22 NM_007317.3 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:11
• Conservation: PhyloP100: 4.33
• Publications: 8 publications found

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]

KIF22 Gene-Disease associations (from GenCC):

• spondyloepimetaphyseal dysplasia with multiple dislocations

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P

ACMG classification

Our verdict: Pathogenic. The variant received 18 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 3 uncertain 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 chr16-29798641-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 988564.Status of the report is criteria_provided_single_submitter, 1 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.971
• PP5: Variant 16-29798641-C-T is Pathogenic according to our data. Variant chr16-29798641-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 30334.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007317.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF22	NM_007317.3	MANE Select	c.443C>T	p.Pro148Leu	missense	Exon 4 of 14	NP_015556.1
	KIF22	NM_001256269.2		c.239C>T	p.Pro80Leu	missense	Exon 5 of 15	NP_001243198.1
	KIF22	NM_001256270.1		c.239C>T	p.Pro80Leu	missense	Exon 4 of 14	NP_001243199.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF22	ENST00000160827.9	TSL:1 MANE Select	c.443C>T	p.Pro148Leu	missense	Exon 4 of 14	ENSP00000160827.5
	KIF22	ENST00000569382.3	TSL:5	c.443C>T	p.Pro148Leu	missense	Exon 4 of 14	ENSP00000456165.3
	KIF22	ENST00000689660.1		c.443C>T	p.Pro148Leu	missense	Exon 4 of 14	ENSP00000509285.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461844 Hom.: 0 Cov.: 36 AF XY: 0.00 AC XY: 0 AN XY: 727228

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53384

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5764

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112006

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Spondyloepimetaphyseal dysplasia with multiple dislocations Pathogenic:7

Oct 31, 2018

Fulgent Genetics, Fulgent Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 09, 2011

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Feb 05, 2025

Victorian Clinical Genetics Services, Murdoch Childrens Research Institute

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is classified as Pathogenic. Evidence in support of pathogenic classification: Variant is absent from gnomAD (v2, v3 and v4); This variant has strong previous evidence of pathogenicity in unrelated individuals. This variant has been classified as likely pathogenic/pathogenic by diagnostic laboratories in ClinVar; Variant is located in a hotspot region or cluster of PATHOGENIC variants (PMIDs: 22152677, 22152678); Missense variant predicted to be damaging by in silico tool(s) or highly conserved with a major amino acid change; This variant has been shown to be de novo in the proband (parental status confirmed) (by trio analysis). Additional information: Variant is predicted to result in a missense amino acid change from proline to leucine; This variant is heterozygous; This gene is associated with autosomal dominant disease; The mechanism of disease for this gene is not clearly established. However, dominant negative and gain of function have been suggested (PMID: 22152678, 35730929).

Sep 26, 2014

Yale Center for Mendelian Genomics, Yale University

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

CENTOGENE GmbH and LLC - Guiding Precision Medicine

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jan 01, 2016

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Likely pathogenic. The following ACMG criteria were applied in classifying this variant: PS1,PM1,PM2,PP3.

Oct 06, 2021

Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderate, PM2 moderate, PM6 very strong, PP1 moderate, PP3 supporting

not provided Pathogenic:3

Sep 23, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 148 of the KIF22 protein (p.Pro148Leu). 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 (PMID: 22152677, 22152678, 25256152). 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: 30334). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on KIF22 protein function. This variant disrupts the p.Pro148 amino acid residue in KIF22. Other variant(s) that disrupt this residue have been observed in individuals with KIF22-related conditions (PMID: 22152677), which suggests that this may be a clinically significant amino acid residue. For these reasons, this variant has been classified as Pathogenic.

Apr 20, 2021

Blueprint Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 13, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 22152677, 25256152, 19277648, 22152678, 28229453, 30138938, 32860008, 27535533)

Inborn genetic diseases Pathogenic:1

Feb 01, 2018

Ambry Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.80
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.30
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.86	D
Eigen	Pathogenic	0.85
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.97	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		4.3
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-9.3	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.027	D
Polyphen		1.0	D
Vest4		0.88
MutPred		0.85		Loss of disorder (P = 0.0479)
MVP		0.93
MPC		0.86
ClinPred		1.0	D
GERP RS		6.0
PromoterAI		0.025	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.80
gMVP		0.86
Mutation Taster		=186/114	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs193922921; hg19: chr16-29809962;