rs56024577

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001244008.2(KIF1A):c.3641-8C>T variant causes a splice region, intron change. The variant allele was found at a frequency of 0.279 in 1,543,814 control chromosomes in the GnomAD database, including 66,318 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 0.24 ( 5486 hom., cov: 33)

Exomes 𝑓: 0.28 ( 60832 hom. )

Consequence

KIF1A
NM_001244008.2 splice_region, intron

Scores

Splicing: ADA: 0.0003042

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: 3.72

Variant links:

Genes affected

KIF1A (HGNC:888): (kinesin family member 1A) The protein encoded by this gene is a member of the kinesin family and functions as an anterograde motor protein that transports membranous organelles along axonal microtubules. Mutations at this locus have been associated with spastic paraplegia-30 and hereditary sensory neuropathy IIC. Alternatively spliced transcript variants encoding distinct isoforms have been described. [provided by RefSeq, Apr 2012]

KIF1A links:

KIF1A (HGNC:):

KIF1A links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

BP6

Variant 2-240741385-G-A is Benign according to our data. Variant chr2-240741385-G-A is described in ClinVar as [Benign]. Clinvar id is 129391.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240741385-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.467 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.3641-8C>T		splice_region_variant, intron_variant		ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.3641-8C>T		splice_region_variant, intron_variant		5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.235

AC:

35771

AN:

152008

Hom.:

5473

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0604

Gnomad AMI

AF:

0.170

Gnomad AMR

AF:

0.346

Gnomad ASJ

AF:

0.234

Gnomad EAS

AF:

0.431

Gnomad SAS

AF:

0.484

Gnomad FIN

AF:

0.335

Gnomad MID

AF:

0.278

Gnomad NFE

AF:

0.270

Gnomad OTH

AF:

0.240

GnomAD3 exomes

AF:

0.347

AC:

57808

AN:

166444

Hom.:

11293

AF XY:

0.352

AC XY:

31512

AN XY:

89606

show subpopulations

Gnomad AFR exome

AF:

0.0590

Gnomad AMR exome

AF:

0.509

Gnomad ASJ exome

AF:

0.247

Gnomad EAS exome

AF:

0.453

Gnomad SAS exome

AF:

0.483

Gnomad FIN exome

AF:

0.364

Gnomad NFE exome

AF:

0.277

Gnomad OTH exome

AF:

0.312

GnomAD4 exome

AF:

0.284

AC:

395390

AN:

1391688

Hom.:

60832

Cov.:

AF XY:

0.291

AC XY:

199666

AN XY:

686874

show subpopulations

Gnomad4 AFR exome

AF:

0.0524

Gnomad4 AMR exome

AF:

0.482

Gnomad4 ASJ exome

AF:

0.244

Gnomad4 EAS exome

AF:

0.424

Gnomad4 SAS exome

AF:

0.478

Gnomad4 FIN exome

AF:

0.339

Gnomad4 NFE exome

AF:

0.264

Gnomad4 OTH exome

AF:

0.281

GnomAD4 genome

AF:

0.235

AC:

35797

AN:

152126

Hom.:

5486

Cov.:

AF XY:

0.247

AC XY:

18348

AN XY:

74372

show subpopulations

Gnomad4 AFR

AF:

0.0603

Gnomad4 AMR

AF:

0.347

Gnomad4 ASJ

AF:

0.234

Gnomad4 EAS

AF:

0.431

Gnomad4 SAS

AF:

0.484

Gnomad4 FIN

AF:

0.335

Gnomad4 NFE

AF:

0.270

Gnomad4 OTH

AF:

0.248

Alfa

AF:

0.202

Hom.:

698

Bravo

AF:

0.227

Asia WGS

AF:

0.438

AC:

1519

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:12

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics, Academic Medical Center	-	- -
Benign, no assertion criteria provided	clinical testing	Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	-	- -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 03, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Hereditary spastic paraplegia 30

Benign:2

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. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Aug 19, 2021	- -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Neuropathy, hereditary sensory, type 2C

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Intellectual disability, autosomal dominant 9

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Aug 19, 2021

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9

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

BayesDel_noAF

Benign

-0.82

CADD

Benign

5.8

DANN

Benign

0.53

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00030

dbscSNV1_RF

Benign

0.0080

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

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