X-70299148-A-G

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_012310.5(KIF4A):c.462A>G(p.Pro154=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00107 in 1,206,001 control chromosomes in the GnomAD database, including 2 homozygotes. There are 452 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., 27 hem., cov: 23)
  • Exomes 𝑓: 0.0011 (2 hom. 425 hem.)
• Consequence: KIF4A NM_012310.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0370

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.5).
• BP6: Variant X-70299148-A-G is Benign according to our data. Variant chrX-70299148-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 773102.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.037 with no splicing effect.
• BS2: High Hemizygotes in GnomAd at 27 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF4A	NM_012310.5	c.462A>G	p.Pro154=	synonymous_variant	5/31	ENST00000374403.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF4A	ENST00000374403.4	c.462A>G	p.Pro154=	synonymous_variant	5/31	1	NM_012310.5	P1

Frequencies

GnomAD3 genomes AF: 0.000767 AC: 86 AN: 112059 Hom.: 0 Cov.: 23 AF XY: 0.000789 AC XY: 27 AN XY: 34225

Gnomad AFR AF: 0.000162

Gnomad AMI AF: 0.00725

Gnomad AMR AF: 0.000284

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00151

Gnomad FIN AF: 0.000165

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00122

Gnomad OTH AF: 0.00199

GnomAD3 exomes AF: 0.000754 AC: 136 AN: 180450 Hom.: 0 AF XY: 0.000983 AC XY: 64 AN XY: 65074

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000188

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00262

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000999

Gnomad OTH exome AF: 0.000450

GnomAD4 exome AF: 0.00110 AC: 1207 AN: 1093889 Hom.: 2 Cov.: 28 AF XY: 0.00118 AC XY: 425 AN XY: 359795

Gnomad4 AFR exome AF: 0.000152

Gnomad4 AMR exome AF: 0.000258

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00313

Gnomad4 FIN exome AF: 0.0000247

Gnomad4 NFE exome AF: 0.00118

Gnomad4 OTH exome AF: 0.000741

GnomAD4 genome AF: 0.000776 AC: 87 AN: 112112 Hom.: 0 Cov.: 23 AF XY: 0.000787 AC XY: 27 AN XY: 34288

Gnomad4 AFR AF: 0.000162

Gnomad4 AMR AF: 0.000284

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00189

Gnomad4 FIN AF: 0.000165

Gnomad4 NFE AF: 0.00122

Gnomad4 OTH AF: 0.00196

Alfa AF: 0.00102 Hom.: 5

Bravo AF: 0.000888

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

May 08, 2018

- -

KIF4A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 20, 2019

This variant is classified as likely 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	-0.50
Cadd	Benign	7.7
Dann	Benign	0.72

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: rs61748977; hg19: chrX-69518998;