rs199529123

Positions:

• chrX-70387248-G-A

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_Moderate BS2

The NM_012310.5(KIF4A):​c.2183G>A​(p.Arg728Gln) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000572 in 1,188,099 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 20 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R728W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000060 (0 hom. 19 hem.)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 9.05

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 Likely_benign. Variant got -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2546246).
• BS2: High Hemizygotes in GnomAdExome4 at 19 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF4A	NM_012310.5	c.2183G>A	p.Arg728Gln	missense_variant	20/31	ENST00000374403.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF4A	ENST00000374403.4	c.2183G>A	p.Arg728Gln	missense_variant	20/31	1	NM_012310.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111577 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33771

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000564

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000683 AC: 10 AN: 146470 Hom.: 0 AF XY: 0.0000880 AC XY: 4 AN XY: 45434

Gnomad AFR exome AF: 0.0000996

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000658

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000129

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000604 AC: 65 AN: 1076470 Hom.: 0 Cov.: 30 AF XY: 0.0000542 AC XY: 19 AN XY: 350528

Gnomad4 AFR exome AF: 0.0000779

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000118

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000686

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111629 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33833

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000564

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.0000339 AC: 4

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

Aug 01, 2022

Variant summary: KIF4A c.2183G>A (p.Arg728Gln) results in a conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 6.8e-05 in 146470 control chromosomes, including 4 hemizygotes (gnomAD). To our knowledge, no occurrence of c.2183G>A in individuals affected with Intellectual Disability, X-Linked 100 and no experimental evidence demonstrating its impact on protein function have been reported. A ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. 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

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Jun 15, 2017

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.13	D
BayesDel_noAF	Uncertain	-0.050
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.19	T
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.81	T
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.037	T
MutationAssessor	Uncertain	2.7	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-2.1	N
REVEL	Uncertain	0.41
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.091	T
Polyphen		1.0	D
Vest4		0.21
MVP		0.96
MPC		0.45
ClinPred		0.28	T
GERP RS		4.6
Varity_R		0.37
gMVP		0.47

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: rs199529123; hg19: chrX-69607098;