rs145983282

chrX-70343712-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012310.5(KIF4A):c.1276G>T(p.Ala426Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,209,912 control chromosomes in the GnomAD database, including 7 homozygotes. There are 314 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A426T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0057 (6 hom., 176 hem., cov: 23)
  • Exomes 𝑓: 0.00052 (1 hom. 138 hem.)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 4.09

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0065947175).
• BP6: Variant X-70343712-G-T is Benign according to our data. Variant chrX-70343712-G-T is described in ClinVar as [Benign]. Clinvar id is 377032.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70343712-G-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00573 (642/112002) while in subpopulation AFR AF= 0.0194 (598/30859). AF 95% confidence interval is 0.0181. There are 6 homozygotes in gnomad4. There are 176 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 6 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF4A	NM_012310.5	c.1276G>T	p.Ala426Ser	missense_variant	12/31	ENST00000374403.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF4A	ENST00000374403.4	c.1276G>T	p.Ala426Ser	missense_variant	12/31	1	NM_012310.5	P1

Frequencies

GnomAD3 genomes AF: 0.00573 AC: 642 AN: 111951 Hom.: 6 Cov.: 23 AF XY: 0.00516 AC XY: 176 AN XY: 34121

Gnomad AFR AF: 0.0194

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00303

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000375

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000751

Gnomad OTH AF: 0.00467

GnomAD3 exomes AF: 0.00168 AC: 307 AN: 183113 Hom.: 4 AF XY: 0.000843 AC XY: 57 AN XY: 67593

Gnomad AFR exome AF: 0.0211

Gnomad AMR exome AF: 0.000767

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000245

Gnomad OTH exome AF: 0.00155

GnomAD4 exome AF: 0.000524 AC: 575 AN: 1097910 Hom.: 1 Cov.: 30 AF XY: 0.000380 AC XY: 138 AN XY: 363270

Gnomad4 AFR exome AF: 0.0184

Gnomad4 AMR exome AF: 0.000739

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000185

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000831

Gnomad4 OTH exome AF: 0.00106

GnomAD4 genome AF: 0.00573 AC: 642 AN: 112002 Hom.: 6 Cov.: 23 AF XY: 0.00515 AC XY: 176 AN XY: 34182

Gnomad4 AFR AF: 0.0194

Gnomad4 AMR AF: 0.00303

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000376

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000751

Gnomad4 OTH AF: 0.00461

Alfa AF: 0.000743 Hom.: 30

Bravo AF: 0.00653

ESP6500AA AF: 0.0235 AC: 90

ESP6500EA AF: 0.000149 AC: 1

ExAC AF: 0.00190 AC: 231

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 31, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Jan 05, 2017	- -

KIF4A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Mar 22, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.76	T
BayesDel_noAF	Benign	-0.85
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.14	T
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Benign	0.77	T
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	2.0	M
MutationTaster	Benign	0.97	D;D
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.092
Sift	Benign	0.11	T
Sift4G	Benign	0.22	T
Polyphen		0.079	B
Vest4		0.15
MVP		0.64
MPC		0.38
ClinPred		0.013	T
GERP RS		5.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.20

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: rs145983282; hg19: chrX-69563562;