rs370378060

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 1P and 5B. PP2BP4_StrongBP6

The NM_001244008.2(KIF1A):​c.3094A>T​(p.Met1032Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000281 in 1,567,732 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00014 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KIF1A
NM_001244008.2 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 0.813
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 -4 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=0.037021905).
BP6
Variant 2-240746147-T-A is Benign according to our data. Variant chr2-240746147-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 532874.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1ANM_001244008.2 linkuse as main transcriptc.3094A>T p.Met1032Leu missense_variant 30/49 ENST00000498729.9 NP_001230937.1 Q12756-3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1AENST00000498729.9 linkuse as main transcriptc.3094A>T p.Met1032Leu missense_variant 30/495 NM_001244008.2 ENSP00000438388.1 Q12756-3

Frequencies

GnomAD3 genomes
AF:
0.000138
AC:
21
AN:
152054
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000507
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
GnomAD3 exomes
AF:
0.0000227
AC:
4
AN:
175828
Hom.:
0
AF XY:
0.0000212
AC XY:
2
AN XY:
94234
show subpopulations
Gnomad AFR exome
AF:
0.000424
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000162
AC:
23
AN:
1415560
Hom.:
0
Cov.:
33
AF XY:
0.0000171
AC XY:
12
AN XY:
699922
show subpopulations
Gnomad4 AFR exome
AF:
0.000526
Gnomad4 AMR exome
AF:
0.0000265
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
9.18e-7
Gnomad4 OTH exome
AF:
0.0000682
GnomAD4 genome
AF:
0.000138
AC:
21
AN:
152172
Hom.:
0
Cov.:
33
AF XY:
0.000188
AC XY:
14
AN XY:
74396
show subpopulations
Gnomad4 AFR
AF:
0.000506
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:
0.000136
ESP6500AA
AF:
0.000498
AC:
2
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.0000169
AC:
2

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsMar 23, 2017The p.M931L variant (also known as c.2791A>T), located in coding exon 27 of the KIF1A gene, results from an A to T substitution at nucleotide position 2791. The methionine at codon 931 is replaced by leucine, an amino acid with highly similar properties. This amino acid position is 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. -
not provided Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingRevvity Omics, RevvityJun 28, 2019- -
Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpDec 27, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.079
BayesDel_addAF
Benign
-0.34
T
BayesDel_noAF
Benign
-0.35
CADD
Benign
17
DANN
Benign
0.86
DEOGEN2
Benign
0.16
T;.;.;.;.;.;.;T;.;.;.;.;.
Eigen
Benign
-0.50
Eigen_PC
Benign
-0.38
FATHMM_MKL
Benign
0.68
D
LIST_S2
Uncertain
0.88
.;D;D;D;D;D;.;D;D;D;D;D;D
M_CAP
Benign
0.026
D
MetaRNN
Benign
0.037
T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Benign
-0.81
T
MutationAssessor
Benign
-0.050
N;.;.;.;.;.;.;N;.;.;.;.;.
PrimateAI
Uncertain
0.54
T
PROVEAN
Benign
-1.4
.;N;N;.;.;.;.;.;.;.;.;.;N
REVEL
Benign
0.12
Sift
Benign
0.42
.;T;T;.;.;.;.;.;.;.;.;.;T
Sift4G
Benign
1.0
.;T;T;.;.;.;.;.;.;.;.;.;.
Polyphen
0.0010
B;.;.;.;.;.;.;B;.;.;.;.;B
Vest4
0.22, 0.17
MutPred
0.26
Gain of glycosylation at S934 (P = 0.1411);.;Gain of glycosylation at S934 (P = 0.1411);.;.;Gain of glycosylation at S934 (P = 0.1411);.;Gain of glycosylation at S934 (P = 0.1411);Gain of glycosylation at S934 (P = 0.1411);.;.;.;.;
MVP
0.22
MPC
0.40
ClinPred
0.054
T
GERP RS
3.2
Varity_R
0.23
gMVP
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.020
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: rs370378060; hg19: chr2-241685564; API