rs121912589

Positions:

• chr12-39332608-T-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP2 PP5

The ENST00000361418.10(KIF21A):​c.2839A>G​(p.Met947Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M947I) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KIF21A ENST00000361418.10 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73

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 Likely_pathogenic. Variant got 8 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 ENST00000361418.10
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-39332607-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2630313.Status of the report is criteria_provided_single_submitter, 1 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.
• PP5: Variant 12-39332608-T-C is Pathogenic according to our data. Variant chr12-39332608-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 2440.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF21A	NM_001173464.2	c.2839A>G	p.Met947Val	missense_variant	20/38	ENST00000361418.10	NP_001166935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF21A	ENST00000361418.10	c.2839A>G	p.Met947Val	missense_variant	20/38	1	NM_001173464.2	ENSP00000354878	A1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Dec 01, 2003

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.090	T;.;.;T;.
Eigen	Uncertain	0.23
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Benign	0.032	D
MetaRNN	Uncertain	0.72	D;D;D;D;D
MetaSVM	Uncertain	-0.029	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.3	.;D;D;D;D
REVEL	Uncertain	0.54
Sift	Uncertain	0.0030	.;D;D;D;D
Sift4G	Uncertain	0.0070	.;D;D;D;D
Polyphen		0.0020, 0.62	.;B;.;P;.
Vest4		0.81, 0.85, 0.82, 0.82
MutPred		0.44		.;.;.;Loss of MoRF binding (P = 0.1243);.;
MVP		0.81
MPC		0.93
ClinPred		0.98	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.2
Varity_R		0.81
gMVP		0.77

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs121912589; hg19: chr12-39726410;