rs143037290

Positions:

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2BP4_StrongBP6BS1BS2

The NM_001244008.2(KIF1A):c.3259C>T(p.Pro1087Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00451 in 1,612,358 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0037 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0046 ( 30 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:14

Conservation

PhyloP100: 3.39

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:

KIF1A (HGNC:):

KIF1A links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -12 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1A. . Gene score misZ 5.1579 (greater than the threshold 3.09). Trascript score misZ 5.0191 (greater than threshold 3.09). GenCC has associacion of gene with neuropathy, hereditary sensory, type 2C, hereditary spastic paraplegia 30, syndromic intellectual disability, intellectual disability, autosomal dominant 9, PEHO syndrome, autosomal dominant non-syndromic intellectual disability, hereditary sensory and autonomic neuropathy type 2.

BP4

Computational evidence support a benign effect (MetaRNN=0.006913662).

BP6

Variant 2-240745853-G-A is Benign according to our data. Variant chr2-240745853-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 196129.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=5}. Variant chr2-240745853-G-A is described in Lovd as [Likely_benign]. Variant chr2-240745853-G-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0037 (563/152278) while in subpopulation NFE AF= 0.00591 (402/68006). AF 95% confidence interval is 0.00543. There are 0 homozygotes in gnomad4. There are 262 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAdExome4 at 30 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.3259C>T	p.Pro1087Ser	missense_variant	31/49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.3259C>T	p.Pro1087Ser	missense_variant	31/49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00369

AC:

562

AN:

152158

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000917

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00458

Gnomad ASJ

AF:

0.00115

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00269

Gnomad FIN

AF:

0.00254

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00590

Gnomad OTH

AF:

0.00430

GnomAD3 exomes

AF:

0.00368

AC:

901

AN:

244548

Hom.:

AF XY:

0.00387

AC XY:

515

AN XY:

133214

show subpopulations

Gnomad AFR exome

AF:

0.00108

Gnomad AMR exome

AF:

0.00287

Gnomad ASJ exome

AF:

0.00244

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00246

Gnomad FIN exome

AF:

0.00174

Gnomad NFE exome

AF:

0.00562

Gnomad OTH exome

AF:

0.00538

GnomAD4 exome

AF:

0.00460

AC:

6714

AN:

1460080

Hom.:

Cov.:

AF XY:

0.00470

AC XY:

3412

AN XY:

726218

show subpopulations

Gnomad4 AFR exome

AF:

0.000687

Gnomad4 AMR exome

AF:

0.00296

Gnomad4 ASJ exome

AF:

0.00234

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00273

Gnomad4 FIN exome

AF:

0.00249

Gnomad4 NFE exome

AF:

0.00524

Gnomad4 OTH exome

AF:

0.00419

GnomAD4 genome

AF:

0.00370

AC:

563

AN:

152278

Hom.:

Cov.:

AF XY:

0.00352

AC XY:

262

AN XY:

74448

show subpopulations

Gnomad4 AFR

AF:

0.000914

Gnomad4 AMR

AF:

0.00457

Gnomad4 ASJ

AF:

0.00115

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00270

Gnomad4 FIN

AF:

0.00254

Gnomad4 NFE

AF:

0.00591

Gnomad4 OTH

AF:

0.00426

Alfa

AF:

0.00466

Hom.:

Bravo

AF:

0.00335

TwinsUK

AF:

0.00378

AC:

ALSPAC

AF:

0.00752

AC:

ESP6500AA

AF:

0.000513

AC:

ESP6500EA

AF:

0.00386

AC:

ExAC

AF:

0.00371

AC:

448

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.00474

EpiControl

AF:

0.00577

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:14

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:7

Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 23, 2019	This variant is associated with the following publications: (PMID: 21376300) -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Likely benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2024	KIF1A: BP4, BS2 -

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Sep 23, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jun 24, 2015	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 07, 2024	- -

Hereditary spastic paraplegia 30

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

Hereditary spastic paraplegia

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2019

- -

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

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

History of neurodevelopmental disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 2019

In silico models in agreement (benign);Sub-population frequency in support of benign classification (not ava blue, manual h-w);Subpopulation frequency in support of benign classification -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.075

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Benign

0.88

DEOGEN2

Benign

0.23

T;.;.;.;.;.;.;T;.;.;.;.;.;.

Eigen

Benign

-0.24

Eigen_PC

Benign

-0.17

FATHMM_MKL

Uncertain

0.81

LIST_S2

Uncertain

0.94

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

M_CAP

Benign

0.059

MetaRNN

Benign

0.0069

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

MetaSVM

Benign

-0.74

MutationAssessor

Benign

1.0

L;.;.;.;.;.;.;L;.;.;.;.;.;.

PrimateAI

Benign

0.41

PROVEAN

Benign

-2.1

.;N;D;.;.;.;.;.;.;.;.;.;D;N

REVEL

Benign

0.11

Sift

Benign

0.27

.;T;T;.;.;.;.;.;.;.;.;.;T;T

Sift4G

Benign

0.31

.;T;T;.;.;.;.;.;.;.;.;.;.;.

Polyphen

0.61

P;.;.;.;.;.;.;P;.;.;.;.;.;P

Vest4

0.24, 0.21

MVP

0.49

MPC

0.44

ClinPred

0.0096

GERP RS

4.2

Varity_R

0.11

gMVP

0.65

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