rs121912588

Variant names:

• chr12-39358326-A-G
• rs121912588
• NM_001173464.2:c.1067T>C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PP3_Moderate PP5

The NM_001173464.2(KIF21A):​c.1067T>C​(p.Met356Thr) 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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. M356L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.93
• 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: Uncertain_significance. The variant received 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.855
• PP5: Variant 12-39358326-A-G is Pathogenic according to our data. Variant chr12-39358326-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2439.Status of the report is no_assertion_criteria_provided, 0 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.1067T>C	p.Met356Thr	missense	Exon 8 of 38	NP_001166935.1
	KIF21A	NM_001378439.1		c.1067T>C	p.Met356Thr	missense	Exon 8 of 38	NP_001365368.1
	KIF21A	NM_001378440.1		c.1067T>C	p.Met356Thr	missense	Exon 8 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.1067T>C	p.Met356Thr	missense	Exon 8 of 38	ENSP00000354878.5
	KIF21A	ENST00000361961.7	TSL:1	c.1067T>C	p.Met356Thr	missense	Exon 8 of 37	ENSP00000354851.3
	KIF21A	ENST00000544797.6	TSL:1	c.1067T>C	p.Met356Thr	missense	Exon 8 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:1

Revision: no assertion criteria provided

Submissions by phenotype

Congenital fibrosis of extraocular muscles type 1 Pathogenic:1

Dec 01, 2003

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.10	T
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.076	D
MetaRNN	Pathogenic	0.85	D
MetaSVM	Uncertain	0.017	D
MutationAssessor	Benign	-0.095	N
PhyloP100		8.9
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-5.1	D
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.96	P
Vest4		0.95
MutPred		0.72		Loss of stability (P = 0.0581)
MVP		0.89
MPC		1.0
ClinPred		0.99	D
GERP RS		4.4
Varity_R		0.83
gMVP		0.57
Mutation Taster		=0/100	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: rs121912588; hg19: chr12-39752128;