chr2-240750452-C-T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_001244008.2(KIF1A):​c.2954G>A​(p.Arg985His) variant causes a missense change. The variant allele was found at a frequency of 0.00000558 in 1,613,594 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R985C) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 34)
Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

8
10
1

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.98

Publications

3 publications found
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 Gene-Disease associations (from GenCC):
  • intellectual disability, autosomal dominant 9
    Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P
  • syndromic intellectual disability
    Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
  • neuropathy, hereditary sensory, type 2C
    Inheritance: AR Classification: DEFINITIVE, STRONG, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P
  • hereditary spastic paraplegia 30
    Inheritance: AR, AD Classification: STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, Orphanet
  • autosomal dominant non-syndromic intellectual disability
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • PEHO syndrome
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
  • hereditary sensory and autonomic neuropathy type 2
    Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.786

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1ANM_001244008.2 linkc.2954G>A p.Arg985His missense_variant Exon 28 of 49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkc.2954G>A p.Arg985His missense_variant Exon 28 of 49 5 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.0000482
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:
0.00000479
AC:
7
AN:
1461344
Hom.:
0
Cov.:
31
AF XY:
0.00000413
AC XY:
3
AN XY:
726984
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
33476
American (AMR)
AF:
0.00
AC:
0
AN:
44704
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26126
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39696
South Asian (SAS)
AF:
0.0000348
AC:
3
AN:
86246
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
53306
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.00000360
AC:
4
AN:
1111666
Other (OTH)
AF:
0.00
AC:
0
AN:
60358
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.454
Heterozygous variant carriers
0
1
1
2
2
3
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
AF:
0.0000131
AC:
2
AN:
152250
Hom.:
0
Cov.:
34
AF XY:
0.00
AC XY:
0
AN XY:
74380
show subpopulations
African (AFR)
AF:
0.0000482
AC:
2
AN:
41474
American (AMR)
AF:
0.00
AC:
0
AN:
15292
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3472
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5198
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4830
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10628
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
68034
Other (OTH)
AF:
0.00
AC:
0
AN:
2094
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.550
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Uncertain:1
Jul 05, 2016
Genetic Services Laboratory, University of Chicago
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Uncertain:1
Sep 23, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 884 of the KIF1A protein (p.Arg884His). This variant is present in population databases (rs772779524, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with KIF1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 435635). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) has been performed for this missense variant. However, the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on 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
Pathogenic
0.91
BayesDel_addAF
Uncertain
0.12
D
BayesDel_noAF
Uncertain
-0.060
CADD
Pathogenic
27
DANN
Pathogenic
1.0
DEOGEN2
Uncertain
0.68
D;.;.;.;.;.;.;D;.;.;.;.;.
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.58
FATHMM_MKL
Uncertain
0.91
D
LIST_S2
Pathogenic
0.98
.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
0.62
D
MetaRNN
Pathogenic
0.79
D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Uncertain
0.48
D
MutationAssessor
Pathogenic
3.0
M;.;.;.;.;.;.;M;.;.;.;.;.
PhyloP100
6.0
PrimateAI
Pathogenic
0.81
D
PROVEAN
Uncertain
-4.3
.;D;D;.;.;.;.;.;.;.;.;.;D
REVEL
Pathogenic
0.66
Sift
Uncertain
0.0010
.;D;D;.;.;.;.;.;.;.;.;.;D
Sift4G
Uncertain
0.0020
.;D;D;.;.;.;.;.;.;.;.;.;.
Polyphen
1.0
D;.;.;.;.;.;.;D;.;.;.;.;D
Vest4
0.83, 0.91
MutPred
0.56
Loss of MoRF binding (P = 0.0668);.;Loss of MoRF binding (P = 0.0668);.;.;Loss of MoRF binding (P = 0.0668);.;Loss of MoRF binding (P = 0.0668);Loss of MoRF binding (P = 0.0668);.;.;.;.;
MVP
0.65
MPC
1.4
ClinPred
1.0
D
GERP RS
4.4
Varity_R
0.60
gMVP
0.81
Mutation Taster
=37/63
disease causing

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

Other links and lift over

dbSNP: rs772779524; hg19: chr2-241689869; COSMIC: COSV100240348; COSMIC: COSV100240348; API