chr2-240788191-G-A

Position:

chr2-240788191-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM1PP2PP5

The NM_001244008.2(KIF1A):c.223C>T(p.Arg75Trp) variant causes a missense change. The variant allele was found at a frequency of 0.0000626 in 1,613,706 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. R75Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000065 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3U:5

Conservation

PhyloP100: 4.16

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 hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001244008.2

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.

PP5

Variant 2-240788191-G-A is Pathogenic according to our data. Variant chr2-240788191-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 191158.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Pathogenic=1, Uncertain_significance=4}. Variant chr2-240788191-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.223C>T	p.Arg75Trp	missense_variant	4/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.223C>T	p.Arg75Trp	missense_variant	4/49	5	NM_001244008.2		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.000377

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000643

AC:

AN:

248744

Hom.:

AF XY:

0.0000888

AC XY:

AN XY:

135104

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:

0.0000327

Gnomad FIN exome

AF:

0.000139

Gnomad NFE exome

AF:

0.000107

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000650

AC:

AN:

1461530

Hom.:

Cov.:

AF XY:

0.0000619

AC XY:

AN XY:

727060

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000116

Gnomad4 FIN exome

AF:

0.000169

Gnomad4 NFE exome

AF:

0.0000729

Gnomad4 OTH exome

AF:

0.0000497

GnomAD4 genome

AF:

0.0000394

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74336

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000377

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000529

ExAC

AF:

0.0000742

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3Uncertain:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Pathogenic:1Uncertain:3

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Mar 15, 2023	Reported previously in the heterozygous state and co-occurring with a homozygous variant in the PTRH2 gene in a patient with severe axonal involvement and features of infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD); however, segregation information was not provided (Charles Bronson et al., 2021); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 27124789, 26125038, 21376300, 21820098, 33717719, 33753861, Isa 2022) -
Likely pathogenic, criteria provided, single submitter	research	Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center	-	- -
Uncertain significance, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 28, 2023	The KIF1A c.223C>T; p.Arg75Trp variant (rs778224699) is reported in an individual with ataxia, dystonia, spasticity and/or myotonia (Abouelhoda 2016) and two individuals with spastic paraplegia (Mereaux 2022), but has also been described in an individual with an alternative molecular explanation for disease (Charles Bronson 2021). This variant is reported in ClinVar (Variation ID: 191158) and is found in the general population with an overall allele frequency of 0.006% (17/280,134 alleles) in the Genome Aggregation Database (v2.1.1). Computational analyses are uncertain whether this variant is neutral or deleterious (REVEL: 0.653). Due to limited information, the clinical significance of the p.Arg75Trp variant is uncertain at this time. References: Abouelhoda et al. Clinical genomics can facilitate countrywide estimation of autosomal recessive disease burden. Genet Med. 2016 Dec;18(12):1244-1249. PMID: 27124789. Charles Bronson S et al. A Novel Synergistic Association of Variants in PTRH2 and KIF1A Relates to a Syndrome of Hereditary Axonopathy, Outer Hair Cell Dysfunction, Intellectual Disability, Pancreatic Lipomatosis, Diabetes, Cerebellar Atrophy, and Vertebral Artery Hypoplasia. Cureus. 2021 Feb 6;13(2):e13174. PMID: 33717719. Mereaux JL et al. Clinical and genetic spectra of 1550 index patients with hereditary spastic paraplegia. Brain. 2022 Apr 29;145(3):1029-1037. PMID: 34983064. -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jul 13, 2022	- -

Intellectual disability, autosomal dominant 9

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Dec 18, 2017

- -

Hereditary spastic paraplegia 30

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Paris Brain Institute, Inserm - ICM

- -

KIF1A-related disorder

Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Sep 26, 2024

The KIF1A c.223C>T variant is predicted to result in the amino acid substitution p.Arg75Trp. This variant was reported in a patient presenting with global developmental delay, intellectual disability, weakness of upper and lower limbs, and diabetes who also carried a loss of function variant in PTRH2 (Charles Bronson. 2021. PubMed ID: 33717719). It's also been seen in patients with autism and hereditary spastic paraplegia (Chen. 2021. PubMed ID: 33753861, Méreaux. 2022. PubMed ID: 34983064).However, Additional information supporting the KIF1A c.223C>T variant's pathogenicity were not provided. This variant is reported in 0.016% of alleles in individuals of European (Finnish) descent in gnomAD. Of note, this variant has been observed in >100 heterozygotes in gnomad v4 (https://gnomad.broadinstitute.org/variant/2-240788191-G-A?dataset=gnomad_r4). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Oct 13, 2023

This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 75 of the KIF1A protein (p.Arg75Trp). This variant is present in population databases (rs778224699, gnomAD 0.02%). This missense change has been observed in individual(s) with clinical features of KIF1A-related conditions (PMID: 27124789, 33717719, 33753861). ClinVar contains an entry for this variant (Variation ID: 191158). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt KIF1A protein function. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.0023

BayesDel_noAF

Uncertain

-0.030

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Pathogenic

0.85

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

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.40

FATHMM_MKL

Uncertain

0.79

LIST_S2

Pathogenic

0.98

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

M_CAP

Uncertain

0.25

MetaRNN

Uncertain

0.66

D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

0.46

MutationAssessor

Uncertain

2.9

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Benign

0.41

PROVEAN

Pathogenic

-4.5

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

REVEL

Pathogenic

0.65

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0040

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

Polyphen

0.98

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

Vest4

0.45, 0.44

MVP

0.71

MPC

1.8

ClinPred

0.81

GERP RS

3.9

Varity_R

0.41

gMVP

0.90

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