Genetic Variant KIF5B:p.Thr843Ala (chr10-32018069-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_004521.3(KIF5B):c.2527A>G(p.Thr843Ala) 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KIF5B
NM_004521.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 8.02

Variant links:

Genes affected

KIF5B (HGNC:6324): (kinesin family member 5B) Enables identical protein binding activity; microtubule binding activity; and microtubule motor activity. Involved in several processes, including lysosome localization; natural killer cell mediated cytotoxicity; and positive regulation of protein localization to plasma membrane. Located in centriolar satellite; cytosol; and vesicle. [provided by Alliance of Genome Resources, Apr 2022]

KIF5B links:

LOC107984219 (HGNC:):

LOC107984219 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.77

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF5B	NM_004521.3 link	c.2527A>G	p.Thr843Ala	missense_variant	Exon 23 of 26	ENST00000302418.5	NP_004512.1	P33176V9HW29Q6P164
KIF5B	XM_047425202.1 link	c.2527A>G	p.Thr843Ala	missense_variant	Exon 23 of 25		XP_047281158.1
KIF5B	XM_047425203.1 link	c.2245A>G	p.Thr749Ala	missense_variant	Exon 24 of 27		XP_047281159.1
LOC107984219	XR_001747415.2 link	n.5397T>C		non_coding_transcript_exon_variant	Exon 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF5B	ENST00000302418.5 link	c.2527A>G	p.Thr843Ala	missense_variant	Exon 23 of 26	1	NM_004521.3	ENSP00000307078.4		P33176
KIF5B	ENST00000493889.1 link	n.324A>G		non_coding_transcript_exon_variant	Exon 4 of 5	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1449586

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

721838

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

May 14, 2024

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.27

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.65

Eigen

Pathogenic

0.73

Eigen_PC

Pathogenic

0.71

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.98

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.77

MetaSVM

Uncertain

0.70

MutationAssessor

Uncertain

2.8

PrimateAI

Pathogenic

0.79

PROVEAN

Uncertain

-4.1

REVEL

Pathogenic

0.72

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.034

Polyphen

0.88

Vest4

0.71

MutPred

0.12

Gain of MoRF binding (P = 0.1099);

MVP

0.86

MPC

0.45

ClinPred

0.99

GERP RS

5.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.61

gMVP

0.51

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over