Genetic Variant NM_012310.5:c.794G>T (chrX-70329420-G-T) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3PP5

The NM_012310.5(KIF4A):c.794G>T(p.Arg265Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars).

Frequency

Genomes: not found (cov: 23)

Consequence

KIF4A
NM_012310.5 missense

Scores

Clinical Significance

Likely pathogenic no assertion criteria provided P:2

Conservation

PhyloP100: 7.45

Publications

1 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: Ambry Genetics, Illumina, G2P, Labcorp Genetics (formerly Invitae)
complex neurodevelopmental disorder with or without congenital anomalies
Inheritance: XL Classification: LIMITED Submitted by: ClinGen

KIF4A links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.795

PP5

Variant X-70329420-G-T is Pathogenic according to our data. Variant chrX-70329420-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 632604.Status of the report is no_assertion_criteria_provided, 0 stars.

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.794G>T	p.Arg265Leu	missense	Exon 8 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.794G>T	p.Arg265Leu	missense	Exon 8 of 31	ENSP00000363524.3	O95239-1
KIF4A	ENST00000924316.1		c.794G>T	p.Arg265Leu	missense	Exon 8 of 32	ENSP00000594375.1
KIF4A	ENST00000859344.1		c.845G>T	p.Arg282Leu	missense	Exon 9 of 32	ENSP00000529403.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

ClinVar submissions

Significance:Likely pathogenic

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

Congenital cerebellar hypoplasia (1)

Hydrocephalus;C0175754:Corpus callosum, agenesis of;C3278923:Ventriculomegaly;C3714581:Multicystic kidney dysplasia;C3890167:Intellectual disability, X-linked 100 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.59

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.27

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.79

MetaSVM

Benign

-0.34

MutationAssessor

Benign

0.67

PhyloP100

7.4

PrimateAI

Pathogenic

0.85

PROVEAN

Uncertain

-4.3

REVEL

Pathogenic

0.65

Sift

Uncertain

0.011

Sift4G

Uncertain

0.039

Polyphen

0.90

Vest4

0.64

MutPred

0.68

Loss of solvent accessibility (P = 0.0299)

MVP

1.0

MPC

2.7

ClinPred

0.99

GERP RS

4.5

Varity_R

0.55

gMVP

0.87

Mutation Taster

=8/92

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.33

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.33

Position offset: -15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over