Genetic Variant NM_001173464.2:c.3029T>C (chr12-39332236-A-G) – ACMG Classification: Uncertain_significance (5 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2PP3_ModeratePP5

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

Scores

Clinical Significance

Pathogenic no assertion criteria provided P:1

Conservation

PhyloP100: 8.99

Publications

8 publications found

Variant links:

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

KIF21A links:

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ACMG classification

Classification was made for transcript

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, 0.917

PP5

Variant 12-39332236-A-G is Pathogenic according to our data. Variant chr12-39332236-A-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2438.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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF21A	NM_001173464.2	MANE Select	c.3029T>C	p.Ile1010Thr	missense	Exon 21 of 38	NP_001166935.1
KIF21A	NM_001378439.1		c.3029T>C	p.Ile1010Thr	missense	Exon 21 of 38	NP_001365368.1
KIF21A	NM_001378440.1		c.3029T>C	p.Ile1010Thr	missense	Exon 21 of 37	NP_001365369.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KIF21A	ENST00000361418.10	TSL:1 MANE Select	c.3029T>C	p.Ile1010Thr	missense	Exon 21 of 38	ENSP00000354878.5
KIF21A	ENST00000361961.7	TSL:1	c.2990T>C	p.Ile997Thr	missense	Exon 20 of 37	ENSP00000354851.3
KIF21A	ENST00000544797.6	TSL:1	c.2990T>C	p.Ile997Thr	missense	Exon 20 of 34	ENSP00000445606.2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

LINK: link

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

0.96

BayesDel_addAF

Pathogenic

0.44

BayesDel_noAF

Pathogenic

0.40

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.23

Eigen

Uncertain

0.56

Eigen_PC

Uncertain

0.62

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

1.0

M_CAP

Uncertain

0.12

MetaRNN

Pathogenic

0.92

MetaSVM

Uncertain

-0.22

MutationAssessor

Uncertain

2.4

PhyloP100

9.0

PrimateAI

Pathogenic

0.82

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.87

Sift

Uncertain

0.0010

Sift4G

Uncertain

0.0040

Polyphen

0.68

Vest4

0.92

MutPred

0.80

Gain of disorder (P = 0.0194)

MVP

0.95

MPC

1.0

ClinPred

0.98

GERP RS

5.8

PromoterAI

0.032

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.73

gMVP

0.73

Mutation Taster

=3/97

disease causing (ClinVar)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over