X-70330186-A-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_012310.5(KIF4A):c.925A>T(p.Met309Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000332 in 1,206,092 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 11 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000027 (0 hom., 1 hem., cov: 23)
  • Exomes 𝑓: 0.000034 (0 hom. 10 hem.)
• Consequence: KIF4A NM_012310.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 8.91

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=0.32220095).
• BP6: Variant X-70330186-A-T is Benign according to our data. Variant chrX-70330186-A-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 3048768.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
• BS2: High Hemizygotes in GnomAdExome at 9 XL gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF4A	NM_012310.5	c.925A>T	p.Met309Leu	missense_variant	9/31	ENST00000374403.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF4A	ENST00000374403.4	c.925A>T	p.Met309Leu	missense_variant	9/31	1	NM_012310.5	P1

Frequencies

GnomAD3 genomes AF: 0.0000269 AC: 3 AN: 111604 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33794

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000286

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000195 AC: 35 AN: 179099 Hom.: 0 AF XY: 0.000141 AC XY: 9 AN XY: 63921

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00131

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: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000338 AC: 37 AN: 1094488 Hom.: 0 Cov.: 28 AF XY: 0.0000278 AC XY: 10 AN XY: 360248

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00100

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000435

GnomAD4 genome AF: 0.0000269 AC: 3 AN: 111604 Hom.: 0 Cov.: 23 AF XY: 0.0000296 AC XY: 1 AN XY: 33794

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000286

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 1

Bravo AF: 0.0000642

ExAC AF: 0.000165 AC: 20

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 03, 2023

The c.925A>T (p.M309L) alteration is located in exon 9 (coding exon 8) of the KIF4A gene. This alteration results from a A to T substitution at nucleotide position 925, causing the methionine (M) at amino acid position 309 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

KIF4A-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

May 23, 2022

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
AlphaMissense	Pathogenic	0.68
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Benign	0.94
DEOGEN2	Uncertain	0.72	D
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.090	D
MetaRNN	Benign	0.32	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.54
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.036	D
Polyphen		0.0050	B
Vest4		0.65
MutPred		0.77		Loss of catalytic residue at M309 (P = 0.0518);
MVP		0.95
MPC		1.3
ClinPred		0.32	T
GERP RS		3.9
Varity_R		0.83
gMVP		0.90

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs764770221; hg19: chrX-69550036;