rs11121552

chr1-10375266-C-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_001365951.3(KIF1B):c.5301C>A(p.Thr1767=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,611,190 control chromosomes in the GnomAD database, including 69,030 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1767T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.24 (5109 hom., cov: 32)
  • Exomes 𝑓: 0.29 (63921 hom.)
• Consequence: KIF1B NM_001365951.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: -0.590

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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.25).
• BP6: Variant 1-10375266-C-A is Benign according to our data. Variant chr1-10375266-C-A is described in ClinVar as [Benign]. Clinvar id is 129401.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10375266-C-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.59 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.305 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.5301C>A	p.Thr1767=	synonymous_variant	48/49	ENST00000676179.1
KIF1B	NM_001365952.1	c.5301C>A	p.Thr1767=	synonymous_variant	48/49
KIF1B	NM_015074.3	c.5163C>A	p.Thr1721=	synonymous_variant	46/47

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.5301C>A	p.Thr1767=	synonymous_variant	48/49		NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.240 AC: 36524 AN: 152076 Hom.: 5097 Cov.: 32

Gnomad AFR AF: 0.0929

Gnomad AMI AF: 0.431

Gnomad AMR AF: 0.312

Gnomad ASJ AF: 0.267

Gnomad EAS AF: 0.277

Gnomad SAS AF: 0.250

Gnomad FIN AF: 0.295

Gnomad MID AF: 0.212

Gnomad NFE AF: 0.298

Gnomad OTH AF: 0.256

GnomAD3 exomes AF: 0.280 AC: 70290 AN: 251460 Hom.: 10372 AF XY: 0.278 AC XY: 37802 AN XY: 135908

Gnomad AFR exome AF: 0.0874

Gnomad AMR exome AF: 0.346

Gnomad ASJ exome AF: 0.271

Gnomad EAS exome AF: 0.285

Gnomad SAS exome AF: 0.237

Gnomad FIN exome AF: 0.295

Gnomad NFE exome AF: 0.296

Gnomad OTH exome AF: 0.268

GnomAD4 exome AF: 0.292 AC: 426426 AN: 1458996 Hom.: 63921 Cov.: 34 AF XY: 0.291 AC XY: 211236 AN XY: 725932

Gnomad4 AFR exome AF: 0.0812

Gnomad4 AMR exome AF: 0.338

Gnomad4 ASJ exome AF: 0.272

Gnomad4 EAS exome AF: 0.251

Gnomad4 SAS exome AF: 0.233

Gnomad4 FIN exome AF: 0.303

Gnomad4 NFE exome AF: 0.304

Gnomad4 OTH exome AF: 0.283

GnomAD4 genome AF: 0.240 AC: 36555 AN: 152194 Hom.: 5109 Cov.: 32 AF XY: 0.241 AC XY: 17959 AN XY: 74400

Gnomad4 AFR AF: 0.0929

Gnomad4 AMR AF: 0.313

Gnomad4 ASJ AF: 0.267

Gnomad4 EAS AF: 0.276

Gnomad4 SAS AF: 0.250

Gnomad4 FIN AF: 0.295

Gnomad4 NFE AF: 0.298

Gnomad4 OTH AF: 0.259

Alfa AF: 0.270 Hom.: 3268

Bravo AF: 0.237

Asia WGS AF: 0.272 AC: 943 AN: 3478

EpiCase AF: 0.298

EpiControl AF: 0.299

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:6

Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 20, 2013	The Thr1721Thr variant in KIF1B: This variant is not expected to have clinical s ignificance because it does not alter an amino acid residue, is not located with in the splice consensus sequence, has been identified in 30% (2585/8600) of Euro pean American chromosomes and 9% (413/4406) of African American chromosomes by t he NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs11 121552). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -
Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 28, 2020	This alteration is classified as 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. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -

Charcot-Marie-Tooth disease Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

-

- -

Pheochromocytoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Neuroblastoma Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Charcot-Marie-Tooth disease type 2 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Charcot-Marie-Tooth disease type 2A1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.25
Cadd	Benign	5.7
Dann	Benign	0.74
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs11121552; hg19: chr1-10435324; COSMIC: COSV55805449;