2-240773155-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 5P and 1B. PM1PM5PP2BP4

The NM_001244008.2(KIF1A):c.1139G>A(p.Arg380Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000496 in 1,613,750 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R380P) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1B:1

Conservation

PhyloP100: 4.76

Variant links:

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM1

In a coiled_coil_region (size 17) in uniprot entity KIF1A_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_001244008.2

PM5

Other missense variant is known to change same aminoacid residue: Variant chr2-240773155-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 574511.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=1, Likely_pathogenic=1}.

PP2

Missense variant where missense usually causes diseases, KIF1A

BP4

Computational evidence support a benign effect (MetaRNN=0.4006514).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.1139G>A	p.Arg380Gln	missense_variant	13/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.1139G>A	p.Arg380Gln	missense_variant	13/49	5	NM_001244008.2		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152194

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:

0.000192

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:

0.00000402

AC:

AN:

248748

Hom.:

AF XY:

0.00000741

AC XY:

AN XY:

135040

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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:

0.00000888

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461556

Hom.:

Cov.:

AF XY:

0.00000550

AC XY:

AN XY:

727082

show subpopulations

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:

0.00000540

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152194

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74356

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000192

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Spastic ataxia

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Molecular Medicine for Neurodegenerative and Neuromuscular Diseases Unit, IRCCS Fondazione Stella Maris

Jul 12, 2021

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Sep 15, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.20

BayesDel_addAF

Benign

-0.014

BayesDel_noAF

Benign

-0.26

Cadd

Pathogenic

Dann

Pathogenic

1.0

DEOGEN2

Uncertain

0.65

D;.;.;.;.;.;.;D;.;.;.;.;.;.

Eigen

Uncertain

0.27

Eigen_PC

Uncertain

0.28

FATHMM_MKL

Benign

0.72

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.40

T;T;T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

-0.061

MutationAssessor

Benign

1.9

M;M;.;.;.;.;.;M;.;.;.;.;M;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.48

Polyphen

0.41

B;.;.;.;.;.;.;B;.;.;.;.;P;.

Vest4

0.52

MutPred

0.39

Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);.;Loss of phosphorylation at T377 (P = 0.1413);Loss of phosphorylation at T377 (P = 0.1413);

MVP

0.67

MPC

2.1

ClinPred

0.96

GERP RS

3.8

Varity_R

0.28

gMVP

0.81

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over