dbSNP rs772129850: KIF4A:p.Lys129Arg (chrX-70297148-A-G) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_012310.5(KIF4A):c.386A>G(p.Lys129Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000174 in 1,209,204 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 7 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000018 ( 0 hom., 1 hem., cov: 23)

Exomes 𝑓: 0.000017 ( 0 hom. 6 hem. )

Consequence

KIF4A
NM_012310.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.89

Publications

0 publications found

Variant links:

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]

KIF4A Gene-Disease associations (from GenCC):

intellectual disability, X-linked 100
Inheritance: XL, Unknown Classification: MODERATE, LIMITED Submitted by: G2P, Illumina, Ambry Genetics, Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder with or without congenital anomalies
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

KIF4A links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.054723024).

BS2

High Hemizygotes in GnomAdExome4 at 6 Unknown,XL gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012310.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF4A	NM_012310.5	MANE Select	c.386A>G	p.Lys129Arg	missense	Exon 4 of 31	NP_036442.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KIF4A	ENST00000374403.4	TSL:1 MANE Select	c.386A>G	p.Lys129Arg	missense	Exon 4 of 31	ENSP00000363524.3	O95239-1
KIF4A	ENST00000924316.1		c.386A>G	p.Lys129Arg	missense	Exon 4 of 32	ENSP00000594375.1
KIF4A	ENST00000859344.1		c.386A>G	p.Lys129Arg	missense	Exon 4 of 32	ENSP00000529403.1

Frequencies

GnomAD3 genomes

AF:

0.0000178

AC:

AN:

112617

Hom.:

Cov.:

show subpopulations

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:

0.0000187

Gnomad OTH

AF:

0.000658

GnomAD2 exomes

AF:

0.0000825

AC:

AN:

181879

AF XY:

0.0000452

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000518

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000123

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000173

AC:

AN:

1096587

Hom.:

Cov.:

AF XY:

0.0000166

AC XY:

AN XY:

362027

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26379

American (AMR)

AF:

0.000342

AC:

AN:

35070

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

19360

East Asian (EAS)

AF:

0.00

AC:

AN:

30199

South Asian (SAS)

AF:

0.00

AC:

AN:

53951

European-Finnish (FIN)

AF:

0.00

AC:

AN:

40530

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4129

European-Non Finnish (NFE)

AF:

0.00000476

AC:

AN:

840931

Other (OTH)

AF:

0.0000652

AC:

AN:

46038

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000178

AC:

AN:

112617

Hom.:

Cov.:

AF XY:

0.0000288

AC XY:

AN XY:

34755

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31045

American (AMR)

AF:

0.00

AC:

AN:

10627

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2653

East Asian (EAS)

AF:

0.00

AC:

AN:

3623

South Asian (SAS)

AF:

0.00

AC:

AN:

2727

European-Finnish (FIN)

AF:

0.00

AC:

AN:

6149

Middle Eastern (MID)

AF:

0.00

AC:

AN:

240

European-Non Finnish (NFE)

AF:

0.0000187

AC:

AN:

53345

Other (OTH)

AF:

0.000658

AC:

AN:

1519

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.425

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0000959

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000247

AC:

ClinVar

ClinVar submissions as Germline

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.55

BayesDel_noAF

Benign

-0.71

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.14

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.41

M_CAP

Benign

0.0066

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.99

MutationAssessor

Benign

-0.38

PhyloP100

1.9

PrimateAI

Benign

0.45

PROVEAN

Benign

-0.18

REVEL

Benign

0.10

Sift

Benign

0.42

Sift4G

Benign

0.69

Polyphen

0.0

Vest4

0.078

MutPred

0.35

Loss of ubiquitination at K129 (P = 0.0297)

MVP

0.64

MPC

1.1

ClinPred

0.038

GERP RS

1.8

Varity_R

0.054

gMVP

0.44

Mutation Taster

=100/0

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over