rs374244985

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 1P and 4B. PP2BP4_Strong

The NM_001244008.2(KIF1A):​c.3680C>T​(p.Pro1227Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000123 in 1,593,606 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict 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. P1227Q) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00012 ( 1 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

3
16

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6B:1

Conservation

PhyloP100: 5.72
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 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=0.022413999).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KIF1ANM_001244008.2 linkuse as main transcriptc.3680C>T p.Pro1227Leu missense_variant 35/49 ENST00000498729.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KIF1AENST00000498729.9 linkuse as main transcriptc.3680C>T p.Pro1227Leu missense_variant 35/495 NM_001244008.2 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152196
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000193
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
Gnomad ASJ
AF:
0.00115
Gnomad EAS
AF:
0.000385
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000735
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.000211
AC:
46
AN:
218374
Hom.:
0
AF XY:
0.000210
AC XY:
25
AN XY:
119068
show subpopulations
Gnomad AFR exome
AF:
0.0000772
Gnomad AMR exome
AF:
0.0000622
Gnomad ASJ exome
AF:
0.000942
Gnomad EAS exome
AF:
0.000904
Gnomad SAS exome
AF:
0.000181
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000140
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000121
AC:
175
AN:
1441292
Hom.:
1
Cov.:
31
AF XY:
0.000136
AC XY:
97
AN XY:
715806
show subpopulations
Gnomad4 AFR exome
AF:
0.0000301
Gnomad4 AMR exome
AF:
0.000210
Gnomad4 ASJ exome
AF:
0.00104
Gnomad4 EAS exome
AF:
0.000384
Gnomad4 SAS exome
AF:
0.000191
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000859
Gnomad4 OTH exome
AF:
0.000201
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152314
Hom.:
0
Cov.:
33
AF XY:
0.000161
AC XY:
12
AN XY:
74470
show subpopulations
Gnomad4 AFR
AF:
0.000192
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00115
Gnomad4 EAS
AF:
0.000386
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000735
Gnomad4 OTH
AF:
0.000473
Alfa
AF:
0.000300
Hom.:
0
Bravo
AF:
0.000151
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000118
AC:
1
ExAC
AF:
0.000257
AC:
31
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:6Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not provided Uncertain:3
Uncertain significance, criteria provided, single submitterclinical testingAthena DiagnosticsNov 03, 2021- -
Uncertain significance, criteria provided, single submitterclinical testingARUP Laboratories, Molecular Genetics and Genomics, ARUP LaboratoriesJul 25, 2019The KIF1A c.3377C>T; p.Pro1126Leu variant (rs374244985), to our knowledge, is not reported in the medical literature but is reported as uncertain in ClinVar (Variation ID: 447653). This variant is listed in the Genome Aggregation Database (gnomAD) with an overall population frequency of 0.1 percent in the Ashkenazi Jewish population (identified on 49 out of 249,768 chromosomes). The proline at position 1126 is weakly conserved and computational analyses of the effects of the p.Pro1126Leu variant on protein structure and function is neutral (SIFT: tolerated, PolyPhen-2: benign). Overall, there is not enough evidence to classify the p.Pro1126Leu variant with certainty. -
Uncertain significance, criteria provided, single submitterclinical testingGeneDxMar 02, 2020In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 22, 2020The p.P1227L variant (also known as c.3680C>T), located in coding exon 34 of the KIF1A gene, results from a C to T substitution at nucleotide position 3680. The proline at codon 1227 is replaced by leucine, an amino acid with similar properties. This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Hereditary spastic paraplegia 30 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJan 13, 2018This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -
Neuropathy, hereditary sensory and autonomic, type 2A;C3280168:Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingFulgent Genetics, Fulgent GeneticsOct 31, 2018- -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Likely benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 19, 2024- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.074
BayesDel_addAF
Benign
-0.32
T
BayesDel_noAF
Benign
-0.31
CADD
Benign
23
DANN
Uncertain
0.98
DEOGEN2
Benign
0.18
T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen
Benign
-0.15
Eigen_PC
Benign
-0.063
FATHMM_MKL
Uncertain
0.89
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D;.;D;D;D;D;D;D;D
M_CAP
Benign
0.040
D
MetaRNN
Benign
0.022
T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
-0.17
N;.;.;.;.;.;.;N;.;.;.;.;.;.
MutationTaster
Benign
1.0
D;D
PrimateAI
Benign
0.46
T
PROVEAN
Benign
-1.5
.;N;N;.;.;.;.;.;.;.;.;.;.;N
REVEL
Benign
0.12
Sift
Benign
0.25
.;T;T;.;.;.;.;.;.;.;.;.;.;T
Sift4G
Benign
0.48
.;T;T;.;.;.;.;.;.;.;.;.;.;.
Polyphen
0.17
B;.;.;.;.;.;.;B;.;.;.;.;.;B
Vest4
0.46, 0.45
MVP
0.56
MPC
0.46
ClinPred
0.043
T
GERP RS
4.3
Varity_R
0.061
gMVP
0.24

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.

Other links and lift over

dbSNP: rs374244985; hg19: chr2-241680755; API