rs1060501913

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_001365951.3(KIF1B):ā€‹c.1507A>Gā€‹(p.Met503Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,456,666 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (ā˜…ā˜…).

Frequency

Genomes: not found (cov: 31)
Exomes š‘“: 6.9e-7 ( 0 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

2
7
10

Clinical Significance

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

Conservation

PhyloP100: 9.20
Variant links:
Genes affected
KIF1B (HGNC:16636): (kinesin family member 1B) Predicted to enable microtubule binding activity and plus-end-directed microtubule motor activity. Predicted to be involved in chemical synaptic transmission; dense core granule cytoskeletal transport; and vesicle-mediated transport. Predicted to act upstream of or within mitochondrion transport along microtubule. Predicted to be located in cytoplasmic vesicle membrane and neuron projection. Predicted to be part of kinesin complex. Predicted to be active in several cellular components, including axon; dendrite; and microtubule. Implicated in Charcot-Marie-Tooth disease type 2A1; carcinoma (multiple); multiple sclerosis; neuroblastoma; and pheochromocytoma. Biomarker of hepatocellular carcinoma. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KIF1B. . Gene score misZ 3.599 (greater than the threshold 3.09). Trascript score misZ 5.2436 (greater than threshold 3.09). GenCC has associacion of gene with pheochromocytoma, neuroblastoma, susceptibility to, 1, hereditary pheochromocytoma-paraganglioma, Charcot-Marie-Tooth disease type 2A1.
BP4
Computational evidence support a benign effect (MetaRNN=0.29689792).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KIF1BNM_001365951.3 linkuse as main transcriptc.1507A>G p.Met503Val missense_variant 16/49 ENST00000676179.1 NP_001352880.1

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KIF1BENST00000676179.1 linkuse as main transcriptc.1507A>G p.Met503Val missense_variant 16/49 NM_001365951.3 ENSP00000502065 P1O60333-1

Frequencies

GnomAD3 genomes
Cov.:
31
GnomAD4 exome
AF:
6.86e-7
AC:
1
AN:
1456666
Hom.:
0
Cov.:
28
AF XY:
0.00000138
AC XY:
1
AN XY:
725060
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.03e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
31

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsJun 11, 2021The p.M457V variant (also known as c.1369A>G), located in coding exon 13 of the KIF1B gene, results from an A to G substitution at nucleotide position 1369. The methionine at codon 457 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -
Charcot-Marie-Tooth disease type 2 Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpAug 27, 2016In summary, this variant is a novel missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a KIF1B-related disease. This sequence change replaces methionine with valine at codon 457 of the KIF1B protein (p.Met457Val). The methionine residue is moderately conserved and there is a small physicochemical difference between methionine and valine. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
0.54
BayesDel_addAF
Uncertain
0.074
D
BayesDel_noAF
Benign
-0.13
CADD
Uncertain
24
DANN
Benign
0.96
DEOGEN2
Benign
0.34
.;.;T;.;.;.;.
Eigen
Uncertain
0.24
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Pathogenic
0.99
D
LIST_S2
Uncertain
0.97
.;D;D;D;D;D;D
M_CAP
Benign
0.0087
T
MetaRNN
Benign
0.30
T;T;T;T;T;T;T
MetaSVM
Benign
-0.58
T
MutationAssessor
Benign
1.4
.;.;L;.;L;.;.
MutationTaster
Benign
1.0
D;D;D;D;D
PrimateAI
Pathogenic
0.84
D
PROVEAN
Uncertain
-3.1
D;N;N;D;N;.;.
REVEL
Uncertain
0.33
Sift
Benign
0.12
T;T;T;T;T;.;.
Sift4G
Benign
0.25
T;T;T;T;T;T;T
Polyphen
0.029
B;P;B;B;.;P;.
Vest4
0.54
MutPred
0.30
.;.;Loss of disorder (P = 0.0748);.;Loss of disorder (P = 0.0748);.;.;
MVP
0.46
MPC
0.92
ClinPred
0.94
D
GERP RS
5.2
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.26
gMVP
0.81

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.080
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: rs1060501913; hg19: chr1-10351212; API