rs78662124

Positions:

• chr1-10365418-A-C
• chr1-10365418-A-G
• chr1-10365418-A-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP2 PP3 BP4_Strong

The NM_001365951.3(KIF1B):​c.4522A>C​(p.Thr1508Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1508A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.32

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]

KIF1B (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• 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.
• PP3: Multiple lines of computational evidence support a deleterious effect 7: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009757936).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.4522A>C	p.Thr1508Pro	missense_variant	43/49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1	c.4522A>C	p.Thr1508Pro	missense_variant	43/49		NP_001352881.1
KIF1B	NM_015074.3	c.4384A>C	p.Thr1462Pro	missense_variant	41/47		NP_055889.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.4522A>C	p.Thr1508Pro	missense_variant	43/49		NM_001365951.3	ENSP00000502065.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 169 AN: 149674 Hom.: 0 Cov.: 31 FAILED QC

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000864

Gnomad ASJ AF: 0.00293

Gnomad EAS AF: 0.000785

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000486

GnomAD3 exomes AF: 0.0623 AC: 11349 AN: 182038 Hom.: 0 AF XY: 0.0672 AC XY: 6470 AN XY: 96344

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.0675

Gnomad SAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0411

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00549 AC: 7815 AN: 1423088 Hom.: 0 Cov.: 34 AF XY: 0.00657 AC XY: 4623 AN XY: 704142

Gnomad4 AFR exome AF: 0.00783

Gnomad4 AMR exome AF: 0.0220

Gnomad4 ASJ exome AF: 0.00814

Gnomad4 EAS exome AF: 0.0133

Gnomad4 SAS exome AF: 0.0121

Gnomad4 FIN exome AF: 0.0244

Gnomad4 NFE exome AF: 0.00326

Gnomad4 OTH exome AF: 0.00382

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00114 AC: 171 AN: 149768 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 112 AN XY: 73042

Gnomad4 AFR AF: 0.000245

Gnomad4 AMR AF: 0.000863

Gnomad4 ASJ AF: 0.00293

Gnomad4 EAS AF: 0.000787

Gnomad4 SAS AF: 0.000636

Gnomad4 FIN AF: 0.000191

Gnomad4 NFE AF: 0.00187

Gnomad4 OTH AF: 0.000482

Alfa AF: 0.0107 Hom.: 0

ExAC AF: 0.0158 AC: 1916

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Aug 18, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	.;D;.;.;.
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D;D;D;D;D
MetaRNN	Benign	0.0098	T;T;T;T;T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.2	.;M;M;.;.
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D;D;D;.;.
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D;D;D;.;.
Sift4G	Uncertain	0.035	D;D;D;D;D
Polyphen		1.0	D;D;.;D;.
Vest4		0.35
MPC		1.4
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.79
gMVP		0.85

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs78662124; hg19: chr1-10425476; COSMIC: COSV55803543; COSMIC: COSV55803543;