rs121912585

Variant names:

• chr12-39332405-G-A
• rs121912585
• NM_001173464.2:c.2860C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-39332405-G-A
• chr12-39332405-G-C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PM5 PP3 PP5_Very_Strong

The NM_001173464.2(KIF21A):​c.2860C>T​(p.Arg954Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,534 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R954Q) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KIF21A NM_001173464.2 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:15
• Conservation: PhyloP100: 6.58
• Publications: 49 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: Laboratory for Molecular Medicine, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae)
• 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: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain 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 chr12-39332404-C-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2437.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82
• PP5: Variant 12-39332405-G-A is Pathogenic according to our data. Variant chr12-39332405-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 2436.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF21A	NM_001173464.2	MANE Select	c.2860C>T	p.Arg954Trp	missense	Exon 21 of 38	NP_001166935.1	Q7Z4S6-1
	KIF21A	NM_001378439.1		c.2860C>T	p.Arg954Trp	missense	Exon 21 of 38	NP_001365368.1	Q7Z4S6-4
	KIF21A	NM_001378440.1		c.2860C>T	p.Arg954Trp	missense	Exon 21 of 37	NP_001365369.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF21A	ENST00000361418.10	TSL:1 MANE Select	c.2860C>T	p.Arg954Trp	missense	Exon 21 of 38	ENSP00000354878.5	Q7Z4S6-1
	KIF21A	ENST00000361961.7	TSL:1	c.2821C>T	p.Arg941Trp	missense	Exon 20 of 37	ENSP00000354851.3	Q7Z4S6-2
	KIF21A	ENST00000544797.6	TSL:1	c.2821C>T	p.Arg941Trp	missense	Exon 20 of 34	ENSP00000445606.2	Q7Z4S6-5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461534 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727096

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111736

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
9	-	-	Congenital fibrosis of extraocular muscles type 1 (9)
4	-	-	not provided (4)
1	-	-	Fibrosis of extraocular muscles, congenital, 3b (1)
1	-	-	KIF21A-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.90
BayesDel_addAF	Pathogenic	0.41	D
BayesDel_noAF	Pathogenic	0.35
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.39	T
Eigen	Uncertain	0.66
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.61	D
MutationAssessor	Uncertain	2.3	M
PhyloP100		6.6
PrimateAI	Pathogenic	0.81	D
PROVEAN	Pathogenic	-7.5	D
REVEL	Pathogenic	0.79
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.91
MutPred		0.38		Loss of ubiquitination at K952 (P = 0.0272)
MVP		0.94
MPC		0.94
ClinPred		1.0	D
GERP RS		3.7
PromoterAI		-0.024	Neutral
Varity_R		0.92
gMVP		0.67
Mutation Taster		=1/99	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: rs121912585; hg19: chr12-39726207; COSMIC: COSV100735326; COSMIC: COSV100735326;