chr12-39332607-A-C

Variant names:

• chr12-39332607-A-C
• rs121912590
• NM_001173464.2:c.2840T>G

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_001173464.2(KIF21A):​c.2840T>G​(p.Met947Arg) 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. M947T) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 30)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• 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 helix (size 34) in uniprot entity KI21A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) 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 chrnull-null-null-null is described in UniProt as null.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.793
• PP5: Variant 12-39332607-A-C is Pathogenic according to our data. Variant chr12-39332607-A-C is described in ClinVar as [Pathogenic]. Clinvar id is 2441.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF21A	NM_001173464.2	c.2840T>G	p.Met947Arg	missense_variant	Exon 20 of 38	ENST00000361418.10	NP_001166935.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF21A	ENST00000361418.10	c.2840T>G	p.Met947Arg	missense_variant	Exon 20 of 38	1	NM_001173464.2	ENSP00000354878.5

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 30

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Pathogenic:1

Dec 26, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2801T>G (p.M934R) alteration is located in exon 19 (coding exon 19) of the KIF21A gene. This alteration results from a T to G substitution at nucleotide position 2801, causing the methionine (M) at amino acid position 934 to be replaced by an arginine (R) for KIF21A-related congenital fibrosis of extraocular muscles; however, its clinical significance for autosomal recessive KIF21A-related arthrogryposis multiplex congenita is uncertain. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant was reported in individual(s) with features consistent with congenital fibrosis of extraocular muscles; in at least one individual, it was determined to be de novo (Yamada, 2003). Other variant(s) at the same codon, c.2801T>C (p.M934T) and c.2802G>A (p.M934I), have been identified in individual(s) with features consistent with congenital fibrosis of extraocular muscles (Yamada, 2005; Yamada, 2004; Jia, 2022). This amino acid position is well conserved in available vertebrate species. This alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, this alteration is classified as pathogenic. -

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 v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T;.;.;T;.
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D
M_CAP	Benign	0.036	D
MetaRNN	Pathogenic	0.79	D;D;D;D;D
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Uncertain	2.3	.;.;.;M;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Pathogenic	-5.3	.;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	.;D;D;D;D
Sift4G	Pathogenic	0.0010	.;D;D;D;D
Polyphen		0.30, 0.87	.;B;.;P;.
Vest4		0.94, 0.94, 0.93, 0.92
MutPred		0.41		.;.;.;Loss of ubiquitination at K952 (P = 0.0416);.;
MVP		0.91
MPC		1.2
ClinPred		1.0	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.8
Varity_R		0.98
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs121912590; hg19: chr12-39726409;