X-70301961-A-T

Position:

• chrX-70301961-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_012310.5(KIF4A):​c.578A>T​(p.Gln193Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 23)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 6.49

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.42306298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF4A	NM_012310.5	c.578A>T	p.Gln193Leu	missense_variant	6/31	ENST00000374403.4	NP_036442.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF4A	ENST00000374403.4	c.578A>T	p.Gln193Leu	missense_variant	6/31	1	NM_012310.5	ENSP00000363524	P1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 23

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 20, 2023

Variant summary: KIF4A c.578A>T (p.Gln193Leu) results in a non-conservative amino acid change located in the Kinesin motor domain (IPR001752) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 183084 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.578A>T in individuals affected with Intellectual Disability, X-Linked 100 and no experimental evidence demonstrating its impact on protein function have been reported. No submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 05, 2023

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.087
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.069	D
MetaRNN	Benign	0.42	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.98	L
MutationTaster	Benign	0.99	D;D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.20
Sift	Benign	0.12	T
Sift4G	Benign	0.28	T
Polyphen		0.0030	B
Vest4		0.27
MutPred		0.51		Gain of catalytic residue at Q193 (P = 0.0082);
MVP		0.79
MPC		1.3
ClinPred		0.92	D
GERP RS		5.1
Varity_R		0.42
gMVP		0.42

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: rs2085806115; hg19: chrX-69521811;