rs796287290

Positions:

• chr1-10267389-A-C
• chr1-10267389-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001365951.3(KIF1B):​c.439A>C​(p.Met147Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,770 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Not reported in ClinVar
• 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]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.439A>C	p.Met147Leu	missense_variant	6/49	ENST00000676179.1	NP_001352880.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.439A>C	p.Met147Leu	missense_variant	6/49		NM_001365951.3	ENSP00000502065	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251382 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135888

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

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: 0.00000137 AC: 2 AN: 1461770 Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1 AN XY: 727200

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: 0.00

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Uncertain	0.042	T
BayesDel_noAF	Uncertain	-0.010
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.68	.;.;D;.;.;.;.
Eigen	Uncertain	0.20
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	.;D;D;D;D;D;D
M_CAP	Benign	0.043	D
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	-0.55	N;N;N;N;N;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-2.9	D;D;D;D;D;.;.
REVEL	Uncertain	0.50
Sift	Benign	0.15	T;T;T;T;T;.;.
Sift4G	Benign	0.35	T;T;T;T;T;T;T
Polyphen		0.11	B;P;B;B;.;P;.
Vest4		0.64
MutPred		0.59		Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);Loss of phosphorylation at Y146 (P = 0.0928);
MVP		0.70
MPC		1.6
ClinPred		0.84	D
GERP RS		5.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.37
gMVP		0.80

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

Other links and lift over

dbSNP: rs796287290; hg19: chr1-10327447;