rs121912587

chr12-39332236-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP2 PP3_Moderate PP5

The NM_001173464.2(KIF21A):c.3029T>C(p.Ile1010Thr) 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 (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.99

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 NM_001173464.2
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, KIF21A
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.917
• PP5: Variant 12-39332236-A-G is Pathogenic according to our data. Variant chr12-39332236-A-G is described in ClinVar as [Pathogenic]. Clinvar id is 2438.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF21A	NM_001173464.2	c.3029T>C	p.Ile1010Thr	missense_variant	21/38	ENST00000361418.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF21A	ENST00000361418.10	c.3029T>C	p.Ile1010Thr	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: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	0.96
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.40
Cadd	Pathogenic	26
Dann	Uncertain	1.0
DEOGEN2	Benign	0.23	T;.;T;.;T;.;T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.92	D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.22	T
MutationTaster	Benign	1.0	A;A;A;A;A
PrimateAI	Pathogenic	0.82	D
Polyphen		0.68, 0.66	.;P;.;.;P;.;.
Vest4		0.92, 0.93, 0.98, 0.90
MutPred		0.80		.;.;.;.;Gain of disorder (P = 0.0194);.;.;
MVP		0.95
MPC		1.0
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.73
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs121912587; hg19: chr12-39726038;