chr1-10365418-A-C

Variant names:

• chr1-10365418-A-C
• rs78662124
• NM_001365951.3:c.4522A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 1P and 6B. PP3 BP4_Strong BP6_Moderate

The NM_001365951.3(KIF1B):​c.4522A>C​(p.Thr1508Pro) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T1508A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0055 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1B NM_001365951.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 9.32
• Publications: 4 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: 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

ACMG classification

Our verdict: Likely_benign. The variant received -5 ACMG points.

• PP3: Multiple lines of computational evidence support a deleterious effect 8: AlphaMissense, BayesDel_addAF, BayesDel_noAF, Cadd, Eigen, phyloP100way_vertebrate, REVEL, REVEL [when max_spliceai, FATHMM_MKL, MetaRNN, MutationTaster was below the threshold]
• BP4: Computational evidence support a benign effect (MetaRNN=0.009757936).
• BP6: Variant 1-10365418-A-C is Benign according to our data. Variant chr1-10365418-A-C is described in ClinVar as Likely_benign. ClinVar VariationId is 435639.Status of the report is criteria_provided_single_submitter, 1 stars.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	NM_001365951.3	MANE Select	c.4522A>C	p.Thr1508Pro	missense	Exon 43 of 49	NP_001352880.1
	KIF1B	NM_001365952.1		c.4522A>C	p.Thr1508Pro	missense	Exon 43 of 49	NP_001352881.1
	KIF1B	NM_015074.3		c.4384A>C	p.Thr1462Pro	missense	Exon 41 of 47	NP_055889.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KIF1B	ENST00000676179.1	MANE Select	c.4522A>C	p.Thr1508Pro	missense	Exon 43 of 49	ENSP00000502065.1
	KIF1B	ENST00000377081.5	TSL:1	c.4522A>C	p.Thr1508Pro	missense	Exon 42 of 48	ENSP00000366284.1
	KIF1B	ENST00000377086.5	TSL:1	c.4522A>C	p.Thr1508Pro	missense	Exon 43 of 49	ENSP00000366290.1

Frequencies

GnomAD3 genomes AF: 0.00113 AC: 169 AN: 149674 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000864

Gnomad ASJ AF: 0.00293

Gnomad EAS AF: 0.000785

Gnomad SAS AF: 0.000636

Gnomad FIN AF: 0.000191

Gnomad MID AF: 0.00968

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.000486

GnomAD2 exomes AF: 0.0623 AC: 11349 AN: 182038 AF XY: 0.0672

Gnomad AFR exome AF: 0.0698

Gnomad AMR exome AF: 0.0323

Gnomad ASJ exome AF: 0.0395

Gnomad EAS exome AF: 0.0675

Gnomad FIN exome AF: 0.0867

Gnomad NFE exome AF: 0.0742

Gnomad OTH exome AF: 0.0411

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00549 AC: 7815 AN: 1423088 Hom.: 0 Cov.: 34 AF XY: 0.00657 AC XY: 4623 AN XY: 704142

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00783 AC: 256 AN: 32700

American (AMR) AF: 0.0220 AC: 888 AN: 40340

Ashkenazi Jewish (ASJ) AF: 0.00814 AC: 201 AN: 24690

East Asian (EAS) AF: 0.0133 AC: 506 AN: 38008

South Asian (SAS) AF: 0.0121 AC: 972 AN: 80198

European-Finnish (FIN) AF: 0.0244 AC: 1174 AN: 48136

Middle Eastern (MID) AF: 0.00396 AC: 21 AN: 5306

European-Non Finnish (NFE) AF: 0.00326 AC: 3571 AN: 1094564

Other (OTH) AF: 0.00382 AC: 226 AN: 59146

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.00114 AC: 171 AN: 149768 Hom.: 0 Cov.: 31 AF XY: 0.00153 AC XY: 112 AN XY: 73042

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000245 AC: 10 AN: 40866

American (AMR) AF: 0.000863 AC: 13 AN: 15068

Ashkenazi Jewish (ASJ) AF: 0.00293 AC: 10 AN: 3418

East Asian (EAS) AF: 0.000787 AC: 4 AN: 5084

South Asian (SAS) AF: 0.000636 AC: 3 AN: 4716

European-Finnish (FIN) AF: 0.000191 AC: 2 AN: 10446

Middle Eastern (MID) AF: 0.0104 AC: 3 AN: 288

European-Non Finnish (NFE) AF: 0.00187 AC: 125 AN: 66906

Other (OTH) AF: 0.000482 AC: 1 AN: 2074

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00951 Hom.: 0

ExAC AF: 0.0158 AC: 1916

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Aug 18, 2016

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.93
BayesDel_addAF	Pathogenic	0.36	D
BayesDel_noAF	Pathogenic	0.28
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.83	D
Eigen	Pathogenic	0.77
Eigen_PC	Pathogenic	0.77
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.97	D
MetaRNN	Benign	0.0098	T
MetaSVM	Uncertain	0.030	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		9.3
PrimateAI	Uncertain	0.72	T
PROVEAN	Uncertain	-4.2	D
REVEL	Pathogenic	0.70
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.035	D
Polyphen		1.0	D
Vest4		0.35
MPC		1.4
ClinPred		0.011	T
GERP RS		5.5
Varity_R		0.79
gMVP		0.85
Mutation Taster		=22/78	disease causing

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

Other links and lift over

dbSNP: rs78662124; hg19: chr1-10425476; COSMIC: COSV55803543; COSMIC: COSV55803543;