rs1045363046

Positions:

• chrX-70374221-T-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012310.5(KIF4A):​c.1745T>A​(p.Leu582His) variant causes a missense change. 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 Uncertain significance (★).

• Frequency: Genomes: not found (cov: 22)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 7.14

Genes affected

KIF4A (HGNC:13339): (kinesin family member 4A) This gene encodes a member of the kinesin 4 subfamily of kinesin related proteins. The encoded protein is an ATP dependent microtubule-based motor protein that is involved in the intracellular transport of membranous organelles. This protein also associates with condensed chromosome arms and may be involved in maintaining chromosome integrity during mitosis. This protein may also be involved in the organization of the central spindle prior to cytokinesis. A pseudogene of this gene is found on chromosome X.[provided by RefSeq, Mar 2010]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.828

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF4A	NM_012310.5	c.1745T>A	p.Leu582His	missense_variant	16/31	ENST00000374403.4	NP_036442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF4A	ENST00000374403.4	c.1745T>A	p.Leu582His	missense_variant	16/31	1	NM_012310.5	ENSP00000363524.3

Frequencies

GnomAD3 genomes Cov.: 22

GnomAD4 exome Cov.: 25

GnomAD4 genome Cov.: 22

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual disability, X-linked 100 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 11, 2023

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing;provider interpretation

Geisinger Autism and Developmental Medicine Institute, Geisinger Health System

Apr 27, 2017

This 7 year old male with autism spectrum disorder, history of developmental delays, hyperkinesis, and self-injurious behaviors was found to carry a maternally inherited missense variant in the KIF4A gene. At the time of report, variants in this gene have not been clearly associated with any known human disease. This variant has not been reported previously in the literature, to our knowledge, but an insertion/deletion variant in KIF4A was identified in a family with multiple males with mild to moderate intellectual disability and late childhood-onset epilepsy (Willemsen et al., 2014). The variant is absent from population databases. Computational models predict the variant to be damaging. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.74	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.59	D
MetaRNN	Pathogenic	0.83	D
MetaSVM	Uncertain	0.19	D
MutationAssessor	Pathogenic	2.9	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-6.0	D
REVEL	Uncertain	0.58
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.18		Gain of helix (P = 0.0496);
MVP		0.89
MPC		1.2
ClinPred		1.0	D
GERP RS		4.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.86
gMVP		0.64

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

Publications

LitVar

Other links and lift over

dbSNP: rs1045363046; hg19: chrX-69594071;