rs143669846

Variant names:

• chr1-10374389-G-A
• rs143669846
• NM_001365951.3:c.5020G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365951.3(KIF1B):​c.5020G>A​(p.Glu1674Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000547 in 1,614,162 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E1674E) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0029 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00030 (3 hom.)
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 9.35
• Publications: 3 publications found

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 Gene-Disease associations (from GenCC):

• pheochromocytoma

  Inheritance: AD Classification: MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• Charcot-Marie-Tooth disease type 2A1

  Inheritance: AD Classification: SUPPORTIVE, LIMITED, NO_KNOWN Submitted by: ClinGen, Orphanet, Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary pheochromocytoma-paraganglioma

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• neuroblastoma, susceptibility to, 1

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.007891476).
• BP6: Variant 1-10374389-G-A is Benign according to our data. Variant chr1-10374389-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 219797.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 440 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365951.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	NM_001365951.3	MANE Select	c.5020G>A	p.Glu1674Lys	missense	Exon 46 of 49	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.5020G>A	p.Glu1674Lys	missense	Exon 46 of 49	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.4882G>A	p.Glu1628Lys	missense	Exon 44 of 47	NP_055889.2	O60333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.5020G>A	p.Glu1674Lys	missense	Exon 46 of 49	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.5020G>A	p.Glu1674Lys	missense	Exon 45 of 48	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.5020G>A	p.Glu1674Lys	missense	Exon 46 of 49	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes AF: 0.00288 AC: 438 AN: 152174 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000720

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: 0.0000294

Gnomad OTH AF: 0.000958

GnomAD2 exomes AF: 0.000736 AC: 185 AN: 251408 AF XY: 0.000508

Gnomad AFR exome AF: 0.0104

Gnomad AMR exome AF: 0.000347

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000264

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000303 AC: 443 AN: 1461870 Hom.: 3 Cov.: 32 AF XY: 0.000250 AC XY: 182 AN XY: 727242

African (AFR) AF: 0.0111 AC: 371 AN: 33480

American (AMR) AF: 0.000447 AC: 20 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000580 AC: 5 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.000347 AC: 2 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1111990

Other (OTH) AF: 0.000530 AC: 32 AN: 60394

GnomAD4 genome AF: 0.00289 AC: 440 AN: 152292 Hom.: 2 Cov.: 32 AF XY: 0.00248 AC XY: 185 AN XY: 74474

African (AFR) AF: 0.0102 AC: 425 AN: 41562

American (AMR) AF: 0.000719 AC: 11 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.000948 AC: 2 AN: 2110

Alfa AF: 0.000968 Hom.: 2

Bravo AF: 0.00313

ESP6500AA AF: 0.0116 AC: 51

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000931 AC: 113

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Charcot-Marie-Tooth disease (1)
-	-	1	Charcot-Marie-Tooth disease type 2 (1)
-	-	1	Neuroblastoma (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.19
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	0.14
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	D
MetaRNN	Benign	0.0079	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	1.5	L
PhyloP100		9.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.22
Sift	Benign	0.20	T
Sift4G	Benign	0.33	T
Polyphen		0.72	P
Vest4		0.75
MVP		0.58
MPC		0.74
ClinPred		0.037	T
GERP RS		5.5
Varity_R		0.23
gMVP		0.46
Mutation Taster		=97/3	polymorphism

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

Other links and lift over

dbSNP: rs143669846; hg19: chr1-10434447;