NM_001173464.2:c.2861G>A

Variant names:

• chr12-39332404-C-T
• rs121912586
• NM_001173464.2:c.2861G>A

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001173464.2(KIF21A):​c.2861G>A​(p.Arg954Gln) variant causes a missense 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. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954W) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:5
• Conservation: PhyloP100: 7.62
• Publications: 17 publications found

Genes affected

KIF21A (HGNC:19349): (kinesin family member 21A) This gene encodes a member of the KIF4 subfamily of kinesin-like motor proteins. The encoded protein is characterized by an N-terminal motor domain a coiled-coil stalk domain and a C-terminal WD-40 repeat domain. This protein may be involved in microtubule dependent transport. Mutations in this gene are the cause of congenital fibrosis of extraocular muscles-1. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Mar 2010]

KIF21A Gene-Disease associations (from GenCC):

• congenital fibrosis of extraocular muscles

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• congenital fibrosis of extraocular muscles type 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, G2P, Laboratory for Molecular Medicine
• arthrogryposis multiplex congenita

  Inheritance: AR Classification: MODERATE Submitted by: Ambry Genetics
• fibrosis of extraocular muscles, congenital, 3b

  Inheritance: AD Classification: LIMITED Submitted by: G2P

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001173464.2
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-39332405-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.
• PP5: Variant 12-39332404-C-T is Pathogenic according to our data. Variant chr12-39332404-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001173464.2. 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
	KIF21A	NM_001173464.2	MANE Select	c.2861G>A	p.Arg954Gln	missense	Exon 21 of 38	NP_001166935.1
	KIF21A	NM_001378439.1		c.2861G>A	p.Arg954Gln	missense	Exon 21 of 38	NP_001365368.1
	KIF21A	NM_001378440.1		c.2861G>A	p.Arg954Gln	missense	Exon 21 of 37	NP_001365369.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF21A	ENST00000361418.10	TSL:1 MANE Select	c.2861G>A	p.Arg954Gln	missense	Exon 21 of 38	ENSP00000354878.5
	KIF21A	ENST00000361961.7	TSL:1	c.2822G>A	p.Arg941Gln	missense	Exon 20 of 37	ENSP00000354851.3
	KIF21A	ENST00000544797.6	TSL:1	c.2822G>A	p.Arg941Gln	missense	Exon 20 of 34	ENSP00000445606.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Pathogenic:2

Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Fibrosis of extraocular muscles, congenital, 3b Pathogenic:1

Mar 01, 2008

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

not provided Pathogenic:1

Jun 09, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; This variant is associated with the following publications: (PMID: 23336411, 21042561, 14595441, 18332320, 15747768)

Abnormality of eye movement Pathogenic:1

Jun 03, 2024

Clinical Genetics Laboratory, Skane University Hospital Lund

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS4, PM2, PM5, PP1, PP3

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.15	T
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		7.6
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0040	D
Polyphen		0.85	P
Vest4		0.81
MutPred		0.32		Loss of MoRF binding (P = 0.0585)
MVP		0.94
MPC		0.96
ClinPred		1.0	D
GERP RS		5.5
PromoterAI		0.0068	Neutral
Varity_R		0.87
gMVP		0.62
Mutation Taster		=1/99	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.66		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.66		Position offset: -2

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

Other links and lift over

dbSNP: rs121912586; hg19: chr12-39726206;