12-39332404-C-T

Position:

• chr12-39332404-C-T

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP2 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:4
• Conservation: PhyloP100: 7.62

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]

ACMG classification

Verdict is Pathogenic. Variant got 16 ACMG points.

• PM1: In a coiled_coil_region (size 88) in uniprot entity KI21A_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) 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 id is 2436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF21A. . Gene score misZ 2.653 (greater than the threshold 3.09). Trascript score misZ 3.1091 (greater than threshold 3.09). GenCC has associacion of gene with congenital fibrosis of extraocular muscles, congenital fibrosis of extraocular muscles type 1.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.788
• PP5: Variant 12-39332404-C-T is Pathogenic according to our data. Variant chr12-39332404-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.2861G>A	p.Arg954Gln	missense_variant	21/38	ENST00000361418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF21A	ENST00000361418.10	c.2861G>A	p.Arg954Gln	missense_variant	21/38	1	NM_001173464.2	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2008	- -
Pathogenic, criteria provided, single submitter	clinical testing	Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	-	- -

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

Pathogenic, no assertion criteria provided

literature only

OMIM

Mar 01, 2008

- -

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 09, 2022

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) -

Computational scores

Source: dbNSFP v4.3

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;.;T;.;T;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D
M_CAP	Uncertain	0.14	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D;D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Uncertain	2.3	.;.;.;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-3.7	.;D;D;D;D;D
REVEL	Pathogenic	0.73
Sift	Uncertain	0.0020	.;D;D;D;D;D
Sift4G	Uncertain	0.0040	.;D;D;D;D;D
Polyphen		0.85, 0.99	.;P;.;.;D;.
Vest4		0.81, 0.79, 0.78, 0.82
MutPred		0.32		.;.;.;.;Loss of MoRF binding (P = 0.0585);.;
MVP		0.94
MPC		0.96
ClinPred		1.0	D
GERP RS		5.5
Varity_R		0.87
gMVP		0.62

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

Publications

LitVar

Other links and lift over

dbSNP: rs121912586; hg19: chr12-39726206;