rs116302604

chr1-10361031-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001365951.3(KIF1B):c.4158G>A(p.Ser1386=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000849 in 1,610,768 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0044 (3 hom., cov: 32)
  • Exomes 𝑓: 0.00048 (3 hom.)
• Consequence: KIF1B NM_001365951.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -3.96

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 1-10361031-G-A is Benign according to our data. Variant chr1-10361031-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 284219.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10361031-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=-3.96 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.000481 (702/1458548) while in subpopulation AFR AF= 0.0169 (564/33402). AF 95% confidence interval is 0.0157. There are 3 homozygotes in gnomad4_exome. There are 289 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd at 665 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.4158G>A	p.Ser1386=	synonymous_variant	39/49	ENST00000676179.1
KIF1B	NM_001365952.1	c.4158G>A	p.Ser1386=	synonymous_variant	39/49
KIF1B	NM_015074.3	c.4020G>A	p.Ser1340=	synonymous_variant	37/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.4158G>A	p.Ser1386=	synonymous_variant	39/49		NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.00437 AC: 665 AN: 152102 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.0147

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00525

GnomAD3 exomes AF: 0.00101 AC: 253 AN: 251462 Hom.: 1 AF XY: 0.000765 AC XY: 104 AN XY: 135908

Gnomad AFR exome AF: 0.0133

Gnomad AMR exome AF: 0.000665

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000653

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000352

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.000481 AC: 702 AN: 1458548 Hom.: 3 Cov.: 31 AF XY: 0.000398 AC XY: 289 AN XY: 725804

Gnomad4 AFR exome AF: 0.0169

Gnomad4 AMR exome AF: 0.000939

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.00118

GnomAD4 genome AF: 0.00438 AC: 666 AN: 152220 Hom.: 3 Cov.: 32 AF XY: 0.00418 AC XY: 311 AN XY: 74434

Gnomad4 AFR AF: 0.0147

Gnomad4 AMR AF: 0.00268

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000208

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00520

Alfa AF: 0.00178 Hom.: 0

Bravo AF: 0.00510

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Apr 01, 2024	KIF1B: BP4, BP7, BS1, BS2 -
Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Nov 18, 2015	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Aug 11, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 24, 2024

- -

KIF1B-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jun 28, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
Cadd	Benign	1.0
Dann	Benign	0.45
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs116302604; hg19: chr1-10421089; COSMIC: COSV55812406; COSMIC: COSV55812406;