Variant rs587778791 details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong

The NM_001244008.2(KIF1A):c.2840delT(p.Leu947fs) variant causes a frameshift change. The variant allele was found at a frequency of 0.0000129 in 1,550,568 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

Frequency

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

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 frameshift

Scores

Not classified

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:5

Conservation

PhyloP100: 4.80

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:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 16 ACMG points.

PVS1

Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.

PP5

Variant 2-240757336-CA-C is Pathogenic according to our data. Variant chr2-240757336-CA-C is described in ClinVar as [Pathogenic]. Clinvar id is 65859.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240757336-CA-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.2840delT	p.Leu947fs	frameshift_variant	27/49	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.2840delT	p.Leu947fs	frameshift_variant	27/49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152210

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000136

AC:

AN:

1398358

Hom.:

Cov.:

AF XY:

0.0000116

AC XY:

AN XY:

689698

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.0000397

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000158

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152210

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74360

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:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000113

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:5

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuropathy, hereditary sensory, type 2C

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 12, 2011	- -
Pathogenic, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Sep 17, 2020	Variant summary: KIF1A c.2555+1023delT (NM_004321.7) is located in the intron 25 of the KIF1A gene. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 150700 control chromosomes (gnomAD and publication data). The KIF1A gene comprises 47 exons plus some alternatively spliced coding exons and has multiple different transcripts. In one of the alternative transcripts (NM_001244008.1) the variant is predicted to cause a frameshift change (c.2840delT, p.Leu947ArgfsX4). Riviere et al (2011) report c.2840delT, in the homozygous and compound heterozygous state, in 4 different families with multiple individuals affected with Hereditary Sensory And Autonomic Neuropathy Type IIC. They specify the variant is located in the alternatively spliced exon 25b and provide evidence that KIF1A exon-25b-containing isoform is strongly expressed in the nervous system. These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. A ClinVar submitter (evaluation after 2014) cites the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic. -

Neuropathy, hereditary sensory and autonomic, type 2A

Pathogenic:1

Pathogenic, no assertion criteria provided

curation

GeneReviews

Nov 23, 2010

- -

KIF1A-related disorder

Pathogenic:1

Pathogenic, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Dec 28, 2023

The KIF1A c.2840delT variant is predicted to result in a frameshift and premature protein termination (p.Leu947Argfs*4). This variant may also be described as ENST00000320389.11 c.2555+1023del, and has been reported to be causative for autosomal recessive hereditary sensory and autonomic neuropathy type II in nine patients from four families (Rivière et al. 2011. PubMed ID: 21820098). This variant has not been reported in a large population database, indicating this variant is rare. Frameshift variants in KIF1A are expected to be pathogenic. This variant is interpreted as pathogenic. -

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

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 01, 2023

ClinVar contains an entry for this variant (Variation ID: 65859). This variant is also known as c.2840delT (p.Leu947Argfs*4). This variant has been observed in individual(s) with autosomal recessive hereditary sensory and autonomic neuropathy (PMID: 21820098). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 24 of the KIF1A gene. It does not directly change the encoded amino acid sequence of the KIF1A protein. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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