1-10232348-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_ModerateBS2

The NM_001365951.3(KIF1B):​c.20A>T​(p.Lys7Met) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000992 in 1,613,600 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 (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

15
3
1

Clinical Significance

Uncertain significance criteria provided, single submitter U:4

Conservation

PhyloP100: 8.65
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 Likely_benign. Variant got -2 ACMG points.

PP3
MetaRNN computational evidence supports a deleterious effect, 0.852
BS2
High AC in GnomAdExome4 at 13 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KIF1BNM_001365951.3 linkc.20A>T p.Lys7Met missense_variant Exon 2 of 49 ENST00000676179.1 NP_001352880.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KIF1BENST00000676179.1 linkc.20A>T p.Lys7Met missense_variant Exon 2 of 49 NM_001365951.3 ENSP00000502065.1 O60333-1

Frequencies

GnomAD3 genomes
AF:
0.0000197
AC:
3
AN:
152218
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
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:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251266
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135786
show subpopulations
Gnomad AFR exome
AF:
0.00
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:
0.0000462
Gnomad NFE exome
AF:
0.00000880
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000890
AC:
13
AN:
1461382
Hom.:
0
Cov.:
30
AF XY:
0.00000550
AC XY:
4
AN XY:
726986
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:
0.0000187
Gnomad4 NFE exome
AF:
0.0000108
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000197
AC:
3
AN:
152218
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74362
show subpopulations
Gnomad4 AFR
AF:
0.00
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:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.00000378
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:4
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not provided Uncertain:3
-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics, Academic Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Uncertain significance
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not specified Uncertain:1
Oct 23, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The p.K7M variant (also known as c.20A>T), located in coding exon 1 of the KIF1B gene, results from an A to T substitution at nucleotide position 20. The lysine at codon 7 is replaced by methionine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. The evidence for this gene-disease relationship is limited; therefore, the clinical significance of this alteration is unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.99
BayesDel_addAF
Pathogenic
0.47
D
BayesDel_noAF
Pathogenic
0.44
CADD
Pathogenic
29
DANN
Uncertain
1.0
DEOGEN2
Pathogenic
0.82
.;.;D;.;.;.;.
Eigen
Pathogenic
0.84
Eigen_PC
Pathogenic
0.81
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.94
.;D;D;D;D;D;D
M_CAP
Uncertain
0.21
D
MetaRNN
Pathogenic
0.85
D;D;D;D;D;D;D
MetaSVM
Pathogenic
0.88
D
MutationAssessor
Pathogenic
3.0
M;M;M;M;M;.;.
PrimateAI
Pathogenic
0.85
D
PROVEAN
Pathogenic
-5.7
D;D;D;D;D;.;.
REVEL
Pathogenic
0.95
Sift
Pathogenic
0.0
D;D;D;D;D;.;.
Sift4G
Pathogenic
0.0
D;D;D;D;D;D;D
Polyphen
1.0
D;D;P;D;.;D;.
Vest4
0.89
MutPred
0.51
Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);Loss of methylation at K7 (P = 0.0209);
MVP
0.93
MPC
2.2
ClinPred
0.99
D
GERP RS
5.4
Varity_R
0.89
gMVP
0.96

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: rs758134092; hg19: chr1-10292406; API