chr1-10210879-G-T

Position:

• chr1-10210879-G-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PVS1_Moderate BP6_Moderate BA1

The NM_001365951.3(KIF1B):​c.-80+1G>T variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0264 in 150,914 control chromosomes in the GnomAD database, including 203 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.026 (203 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KIF1B NM_001365951.3 splice_donor
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.10

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 -8 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.056503393 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.
• BP6: Variant 1-10210879-G-T is Benign according to our data. Variant chr1-10210879-G-T is described in ClinVar as [Benign]. Clinvar id is 291461.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0876 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1B	NM_001365951.3	c.-80+1G>T		splice_donor_variant		ENST00000676179.1	NP_001352880.1
KIF1B	NM_015074.3	c.-80+1G>T		splice_donor_variant			NP_055889.2
KIF1B	NM_183416.4	c.-80+1G>T		splice_donor_variant			NP_904325.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1B	ENST00000676179.1	c.-80+1G>T		splice_donor_variant			NM_001365951.3	ENSP00000502065	P1

Frequencies

GnomAD3 genomes AF: 0.0264 AC: 3981 AN: 150806 Hom.: 204 Cov.: 32

Gnomad AFR AF: 0.0901

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0127

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.0261

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 24 Hom.: 0 Cov.: 0 AF XY: 0.00 AC XY: 0 AN XY: 16

Gnomad4 NFE exome AF: 0.00

GnomAD4 genome AF: 0.0264 AC: 3987 AN: 150914 Hom.: 203 Cov.: 32 AF XY: 0.0254 AC XY: 1874 AN XY: 73696

Gnomad4 AFR AF: 0.0900

Gnomad4 AMR AF: 0.0126

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000178

Gnomad4 OTH AF: 0.0259

Alfa AF: 0.000647 Hom.: 0

Asia WGS AF: 0.00476 AC: 15 AN: 3164

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
CADD	Pathogenic	31
DANN	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.99		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.64		Position offset: -2
DS_DL_spliceai		0.99		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs140240544; hg19: chr1-10270937;