rs72867431

Positions:

• chr1-10371271-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001365951.3(KIF1B):​c.4946+9C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0267 in 1,613,834 control chromosomes in the GnomAD database, including 781 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.036 (116 hom., cov: 31)
  • Exomes 𝑓: 0.026 (665 hom.)
• Consequence: KIF1B NM_001365951.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.00900

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 1-10371271-C-T is Benign according to our data. Variant chr1-10371271-C-T is described in ClinVar as [Benign]. Clinvar id is 291583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-10371271-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0753 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1B	NM_001365951.3	c.4946+9C>T		intron_variant		ENST00000676179.1
KIF1B	NM_001365952.1	c.4946+9C>T		intron_variant
KIF1B	NM_015074.3	c.4808+9C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1B	ENST00000676179.1	c.4946+9C>T		intron_variant			NM_001365951.3	P1

Frequencies

GnomAD3 genomes AF: 0.0355 AC: 5402 AN: 152118 Hom.: 114 Cov.: 31

Gnomad AFR AF: 0.0481

Gnomad AMI AF: 0.0428

Gnomad AMR AF: 0.0323

Gnomad ASJ AF: 0.0521

Gnomad EAS AF: 0.0811

Gnomad SAS AF: 0.0267

Gnomad FIN AF: 0.0502

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.0219

Gnomad OTH AF: 0.0407

GnomAD3 exomes AF: 0.0335 AC: 8417 AN: 251330 Hom.: 167 AF XY: 0.0324 AC XY: 4406 AN XY: 135840

Gnomad AFR exome AF: 0.0495

Gnomad AMR exome AF: 0.0294

Gnomad ASJ exome AF: 0.0466

Gnomad EAS exome AF: 0.0823

Gnomad SAS exome AF: 0.0242

Gnomad FIN exome AF: 0.0464

Gnomad NFE exome AF: 0.0232

Gnomad OTH exome AF: 0.0375

GnomAD4 exome AF: 0.0257 AC: 37634 AN: 1461598 Hom.: 665 Cov.: 33 AF XY: 0.0257 AC XY: 18658 AN XY: 727128

Gnomad4 AFR exome AF: 0.0505

Gnomad4 AMR exome AF: 0.0306

Gnomad4 ASJ exome AF: 0.0466

Gnomad4 EAS exome AF: 0.0884

Gnomad4 SAS exome AF: 0.0258

Gnomad4 FIN exome AF: 0.0464

Gnomad4 NFE exome AF: 0.0203

Gnomad4 OTH exome AF: 0.0342

GnomAD4 genome AF: 0.0355 AC: 5408 AN: 152236 Hom.: 116 Cov.: 31 AF XY: 0.0364 AC XY: 2711 AN XY: 74424

Gnomad4 AFR AF: 0.0480

Gnomad4 AMR AF: 0.0322

Gnomad4 ASJ AF: 0.0521

Gnomad4 EAS AF: 0.0817

Gnomad4 SAS AF: 0.0267

Gnomad4 FIN AF: 0.0502

Gnomad4 NFE AF: 0.0219

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0296 Hom.: 35

Bravo AF: 0.0358

Asia WGS AF: 0.0630 AC: 220 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	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. -

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 12, 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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	8.3
DANN	Benign	0.55

Splicing

Name	Calibrated prediction	Score	Prediction
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

LitVar

Other links and lift over

dbSNP: rs72867431; hg19: chr1-10431329; COSMIC: COSV55809283; COSMIC: COSV55809283;