NM_001365951.3:c.4055+6A>G

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001365951.3(KIF1B):c.4055+6A>G variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00122 in 1,604,990 control chromosomes in the GnomAD database, including 17 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 Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 8 hom., cov: 32)

Exomes 𝑓: 0.00067 ( 9 hom. )

Consequence

KIF1B
NM_001365951.3 splice_region, intron

Scores

Splicing: ADA: 0.0001569

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: -0.137

Publications

1 publications found

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 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: Ambry Genetics, ClinGen, Orphanet, 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

KIF1B links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.84).

BP6

Variant 1-10352742-A-G is Benign according to our data. Variant chr1-10352742-A-G is described in ClinVar as Benign. ClinVar VariationId is 240958.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 = 0.00651 (991/152284) while in subpopulation AFR AF = 0.0225 (935/41550). AF 95% confidence interval is 0.0213. There are 8 homozygotes in GnomAd4. There are 485 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 991 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
KIF1B	NM_001365951.3 link	c.4055+6A>G	splice_region_variant, intron_variant	Intron 38 of 48	ENST00000676179.1	NP_001352880.1
KIF1B	NM_001365952.1 link	c.4055+6A>G	splice_region_variant, intron_variant	Intron 38 of 48		NP_001352881.1
KIF1B	NM_015074.3 link	c.3917+6A>G	splice_region_variant, intron_variant	Intron 36 of 46		NP_055889.2	O60333-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1 link	c.4055+6A>G		splice_region_variant, intron_variant	Intron 38 of 48		NM_001365951.3	ENSP00000502065.1		O60333-1

Frequencies

GnomAD3 genomes

AF:

0.00649

AC:

987

AN:

152166

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0225

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00255

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:

0.0000441

Gnomad OTH

AF:

0.00622

GnomAD2 exomes

AF:

0.00181

AC:

454

AN:

251246

AF XY:

0.00119

show subpopulations

Gnomad AFR exome

AF:

0.0253

Gnomad AMR exome

AF:

0.00107

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000653

GnomAD4 exome

AF:

0.000670

AC:

974

AN:

1452706

Hom.:

Cov.:

AF XY:

0.000565

AC XY:

409

AN XY:

723344

show subpopulations

African (AFR)

AF:

0.0251

AC:

835

AN:

33292

American (AMR)

AF:

0.00119

AC:

AN:

44702

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26076

East Asian (EAS)

AF:

0.00

AC:

AN:

39652

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86062

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53228

Middle Eastern (MID)

AF:

0.000348

AC:

AN:

5742

European-Non Finnish (NFE)

AF:

0.00000906

AC:

AN:

1103910

Other (OTH)

AF:

0.00122

AC:

AN:

60042

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

107

160

214

267

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

112

140

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00651

AC:

991

AN:

152284

Hom.:

Cov.:

AF XY:

0.00651

AC XY:

485

AN XY:

74464

show subpopulations

African (AFR)

AF:

0.0225

AC:

935

AN:

41550

American (AMR)

AF:

0.00261

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.00

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

68026

Other (OTH)

AF:

0.00616

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

109

163

218

272

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00411

Hom.:

Bravo

AF:

0.00767

Asia WGS

AF:

0.00289

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Charcot-Marie-Tooth disease

Benign:1

Molecular Genetics Laboratory, London Health Sciences Centre

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Neuroblastoma

Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Benign:1

Mar 04, 2021

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

-0.14

PromoterAI

-0.013

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=98/2

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00016

dbscSNV1_RF

Benign

0.072

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over