1-10368512-G-A

Position:

chr1-10368512-G-A

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365951.3(KIF1B):c.4798G>A(p.Val1600Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0142 in 1,613,930 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.011 ( 13 hom., cov: 32)

Exomes 𝑓: 0.015 ( 164 hom. )

Consequence

KIF1B
NM_001365951.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 3.40

Variant links:

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 links:

KIF1B (HGNC:):

KIF1B links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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.

BP4

Computational evidence support a benign effect (MetaRNN=0.0055160522).

BP6

Variant 1-10368512-G-A is Benign according to our data. Variant chr1-10368512-G-A is described in ClinVar as [Benign]. Clinvar id is 240959.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10368512-G-A is described in Lovd as [Benign]. Variant chr1-10368512-G-A is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0107 (1631/152292) while in subpopulation NFE AF= 0.0179 (1218/68032). AF 95% confidence interval is 0.0171. There are 13 homozygotes in gnomad4. There are 757 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High AC in GnomAd4 at 1631 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3 linkuse as main transcript	c.4798G>A	p.Val1600Met	missense_variant	44/49	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1 linkuse as main transcript	c.4798G>A	p.Val1600Met	missense_variant	44/49		NP_001352881.1
KIF1B	NM_015074.3 linkuse as main transcript	c.4660G>A	p.Val1554Met	missense_variant	42/47		NP_055889.2	O60333-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 linkuse as main transcript	c.4798G>A	p.Val1600Met	missense_variant	44/49		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

AF:

0.0107

AC:

1630

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00278

Gnomad AMI

AF:

0.0164

Gnomad AMR

AF:

0.00674

Gnomad ASJ

AF:

0.00404

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00290

Gnomad FIN

AF:

0.0122

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0179

Gnomad OTH

AF:

0.0105

GnomAD3 exomes

AF:

0.00994

AC:

2500

AN:

251470

Hom.:

AF XY:

0.0102

AC XY:

1393

AN XY:

135910

show subpopulations

Gnomad AFR exome

AF:

0.00160

Gnomad AMR exome

AF:

0.00301

Gnomad ASJ exome

AF:

0.00496

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00193

Gnomad FIN exome

AF:

0.0130

Gnomad NFE exome

AF:

0.0169

Gnomad OTH exome

AF:

0.00847

GnomAD4 exome

AF:

0.0146

AC:

21285

AN:

1461638

Hom.:

164

Cov.:

AF XY:

0.0143

AC XY:

10421

AN XY:

727140

show subpopulations

Gnomad4 AFR exome

AF:

0.00212

Gnomad4 AMR exome

AF:

0.00371

Gnomad4 ASJ exome

AF:

0.00451

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00225

Gnomad4 FIN exome

AF:

0.0132

Gnomad4 NFE exome

AF:

0.0173

Gnomad4 OTH exome

AF:

0.0123

GnomAD4 genome

AF:

0.0107

AC:

1631

AN:

152292

Hom.:

Cov.:

AF XY:

0.0102

AC XY:

757

AN XY:

74480

show subpopulations

Gnomad4 AFR

AF:

0.00277

Gnomad4 AMR

AF:

0.00673

Gnomad4 ASJ

AF:

0.00404

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00290

Gnomad4 FIN

AF:

0.0122

Gnomad4 NFE

AF:

0.0179

Gnomad4 OTH

AF:

0.0104

Alfa

AF:

0.0151

Hom.:

Bravo

AF:

0.00967

TwinsUK

AF:

0.0178

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.00182

AC:

ESP6500EA

AF:

0.0169

AC:

145

ExAC

AF:

0.0101

AC:

1231

EpiCase

AF:

0.0146

EpiControl

AF:

0.0137

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
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. -

not provided

Benign:3

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 30, 2023	- -

Charcot-Marie-Tooth disease

Benign:1

Benign, criteria provided, single submitter

clinical testing

Molecular Genetics Laboratory, London Health Sciences Centre

- -

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

Labcorp Genetics (formerly Invitae), Labcorp

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.44

BayesDel_noAF

Benign

-0.39

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.33

.;T;.;.;.

Eigen

Benign

-0.16

Eigen_PC

Benign

0.0055

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.91

D;D;D;D;D

MetaRNN

Benign

0.0055

T;T;T;T;T

MetaSVM

Benign

-0.83

MutationAssessor

Uncertain

2.0

.;M;M;.;.

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-0.59

N;N;N;.;.

REVEL

Benign

0.061

Sift

Benign

0.076

T;T;T;.;.

Sift4G

Benign

0.14

T;T;T;T;T

Polyphen

0.0050

B;B;.;B;.

Vest4

0.28

MPC

0.43

ClinPred

0.0054

GERP RS

4.4

Varity_R

0.074

gMVP

0.54

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over