rs114266141

Variant names:

• chr1-10347833-A-C
• rs114266141
• NM_001365951.3:c.3864+6A>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001365951.3(KIF1B):​c.3864+6A>C variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00142 in 1,608,656 control chromosomes in the GnomAD database, including 18 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0067 (11 hom., cov: 32)
  • Exomes 𝑓: 0.00087 (7 hom.)
• Consequence: KIF1B NM_001365951.3 splice_region, intron
• Scores: Splicing: ADA: 0.0009860
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.0340
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.7).
• BP6: Variant 1-10347833-A-C is Benign according to our data. Variant chr1-10347833-A-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 291575.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00672 (1024/152324) while in subpopulation AFR AF = 0.0222 (922/41570). AF 95% confidence interval is 0.021. There are 11 homozygotes in GnomAd4. There are 492 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1024 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.3864+6A>C		splice_region intron	N/A	NP_001352880.1	O60333-1
	KIF1B	NM_001365952.1		c.3864+6A>C		splice_region intron	N/A	NP_001352881.1	O60333-1
	KIF1B	NM_015074.3		c.3726+6A>C		splice_region intron	N/A	NP_055889.2	O60333-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.3864+6A>C		splice_region intron	N/A	ENSP00000502065.1	O60333-1
	KIF1B	ENST00000377081.5	TSL:1	c.3864+6A>C		splice_region intron	N/A	ENSP00000366284.1	O60333-4
	KIF1B	ENST00000377086.5	TSL:1	c.3864+6A>C		splice_region intron	N/A	ENSP00000366290.1	O60333-1

Frequencies

GnomAD3 genomes AF: 0.00668 AC: 1016 AN: 152206 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.0221

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00347

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00335

GnomAD2 exomes AF: 0.00207 AC: 520 AN: 251386 AF XY: 0.00167

Gnomad AFR exome AF: 0.0236

Gnomad AMR exome AF: 0.00121

Gnomad ASJ exome AF: 0.00506

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000273

Gnomad OTH exome AF: 0.00130

GnomAD4 exome AF: 0.000869 AC: 1265 AN: 1456332 Hom.: 7 Cov.: 29 AF XY: 0.000777 AC XY: 563 AN XY: 724834

African (AFR) AF: 0.0232 AC: 775 AN: 33390

American (AMR) AF: 0.00128 AC: 57 AN: 44686

Ashkenazi Jewish (ASJ) AF: 0.00522 AC: 136 AN: 26032

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.000163 AC: 14 AN: 86142

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53380

Middle Eastern (MID) AF: 0.00122 AC: 7 AN: 5750

European-Non Finnish (NFE) AF: 0.000123 AC: 136 AN: 1107140

Other (OTH) AF: 0.00233 AC: 140 AN: 60154

GnomAD4 genome AF: 0.00672 AC: 1024 AN: 152324 Hom.: 11 Cov.: 32 AF XY: 0.00660 AC XY: 492 AN XY: 74490

African (AFR) AF: 0.0222 AC: 922 AN: 41570

American (AMR) AF: 0.00346 AC: 53 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00490 AC: 17 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0374 AC: 11 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68026

Other (OTH) AF: 0.00331 AC: 7 AN: 2112

Alfa AF: 0.00350 Hom.: 2

Bravo AF: 0.00746

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.70
CADD	Benign	13
DANN	Benign	0.76
PhyloP100		-0.034
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00099
dbscSNV1_RF	Benign	0.084
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: rs114266141; hg19: chr1-10407891;