X-70330230-A-G

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_012310.5(KIF4A):c.969A>G(p.Thr323=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0225 in 1,209,497 control chromosomes in the GnomAD database, including 944 homozygotes. There are 8,921 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.032 (123 hom., 997 hem., cov: 23)
  • Exomes 𝑓: 0.022 (821 hom. 7924 hem.)
• Consequence: KIF4A NM_012310.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.109

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.65).
• BP6: Variant X-70330230-A-G is Benign according to our data. Variant chrX-70330230-A-G is described in ClinVar as [Benign]. Clinvar id is 1300074.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chrX-70330230-A-G is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-0.109 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.246 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF4A	NM_012310.5	c.969A>G	p.Thr323=	synonymous_variant	9/31	ENST00000374403.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF4A	ENST00000374403.4	c.969A>G	p.Thr323=	synonymous_variant	9/31	1	NM_012310.5	P1

Frequencies

GnomAD3 genomes AF: 0.0316 AC: 3538 AN: 111829 Hom.: 123 Cov.: 23 AF XY: 0.0293 AC XY: 995 AN XY: 33987

Gnomad AFR AF: 0.0541

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0103

Gnomad ASJ AF: 0.0188

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.0508

Gnomad FIN AF: 0.00693

Gnomad MID AF: 0.00418

Gnomad NFE AF: 0.0110

Gnomad OTH AF: 0.0245

GnomAD3 exomes AF: 0.0378 AC: 6921 AN: 183010 Hom.: 440 AF XY: 0.0354 AC XY: 2393 AN XY: 67586

Gnomad AFR exome AF: 0.0559

Gnomad AMR exome AF: 0.00463

Gnomad ASJ exome AF: 0.0207

Gnomad EAS exome AF: 0.278

Gnomad SAS exome AF: 0.0450

Gnomad FIN exome AF: 0.00875

Gnomad NFE exome AF: 0.0115

Gnomad OTH exome AF: 0.0266

GnomAD4 exome AF: 0.0216 AC: 23687 AN: 1097612 Hom.: 821 Cov.: 29 AF XY: 0.0218 AC XY: 7924 AN XY: 363106

Gnomad4 AFR exome AF: 0.0539

Gnomad4 AMR exome AF: 0.00460

Gnomad4 ASJ exome AF: 0.0215

Gnomad4 EAS exome AF: 0.233

Gnomad4 SAS exome AF: 0.0438

Gnomad4 FIN exome AF: 0.00757

Gnomad4 NFE exome AF: 0.0122

Gnomad4 OTH exome AF: 0.0368

GnomAD4 genome AF: 0.0317 AC: 3542 AN: 111885 Hom.: 123 Cov.: 23 AF XY: 0.0293 AC XY: 997 AN XY: 34053

Gnomad4 AFR AF: 0.0541

Gnomad4 AMR AF: 0.0102

Gnomad4 ASJ AF: 0.0188

Gnomad4 EAS AF: 0.260

Gnomad4 SAS AF: 0.0495

Gnomad4 FIN AF: 0.00693

Gnomad4 NFE AF: 0.0110

Gnomad4 OTH AF: 0.0281

Alfa AF: 0.0210 Hom.: 162

Bravo AF: 0.0351

EpiCase AF: 0.00988

EpiControl AF: 0.0108

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Intellectual disability, X-linked 100 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

KIF4A-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 11, 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
BayesDel_noAF	Benign	-0.65
Cadd	Benign	8.1
Dann	Benign	0.70

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: rs5936873; hg19: chrX-69550080; COSMIC: COSV65542188;