rs2241683

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BA1

The NM_001244008.2(KIF1A):c.4143G>A(p.Pro1381=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0158 in 1,612,268 control chromosomes in the GnomAD database, including 3,093 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.025 ( 376 hom., cov: 32)

Exomes 𝑓: 0.015 ( 2717 hom. )

Consequence

KIF1A
NM_001244008.2 synonymous

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -5.14

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 2-240725384-C-T is Benign according to our data. Variant chr2-240725384-C-T is described in ClinVar as [Benign]. Clinvar id is 129393.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-240725384-C-T is described in Lovd as [Benign].

BP7

Synonymous conserved (PhyloP=-5.14 with no splicing effect.

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.293 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2 linkuse as main transcript	c.4143G>A	p.Pro1381=	synonymous_variant	40/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9 linkuse as main transcript	c.4143G>A	p.Pro1381=	synonymous_variant	40/49	5	NM_001244008.2		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.0250

AC:

3808

AN:

152168

Hom.:

374

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0929

Gnomad ASJ

AF:

0.00173

Gnomad EAS

AF:

0.306

Gnomad SAS

AF:

0.0116

Gnomad FIN

AF:

0.00339

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.00137

Gnomad OTH

AF:

0.0273

GnomAD3 exomes

AF:

0.0392

AC:

9686

AN:

246782

Hom.:

1031

AF XY:

0.0339

AC XY:

4559

AN XY:

134460

show subpopulations

Gnomad AFR exome

AF:

0.0143

Gnomad AMR exome

AF:

0.106

Gnomad ASJ exome

AF:

0.00221

Gnomad EAS exome

AF:

0.292

Gnomad SAS exome

AF:

0.00692

Gnomad FIN exome

AF:

0.00429

Gnomad NFE exome

AF:

0.00103

Gnomad OTH exome

AF:

0.0273

GnomAD4 exome

AF:

0.0148

AC:

21641

AN:

1459982

Hom.:

2717

Cov.:

AF XY:

0.0141

AC XY:

10234

AN XY:

726232

show subpopulations

Gnomad4 AFR exome

AF:

0.0130

Gnomad4 AMR exome

AF:

0.105

Gnomad4 ASJ exome

AF:

0.00188

Gnomad4 EAS exome

AF:

0.337

Gnomad4 SAS exome

AF:

0.00732

Gnomad4 FIN exome

AF:

0.00378

Gnomad4 NFE exome

AF:

0.000718

Gnomad4 OTH exome

AF:

0.0243

GnomAD4 genome

AF:

0.0251

AC:

3823

AN:

152286

Hom.:

376

Cov.:

AF XY:

0.0281

AC XY:

2096

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.0138

Gnomad4 AMR

AF:

0.0934

Gnomad4 ASJ

AF:

0.00173

Gnomad4 EAS

AF:

0.305

Gnomad4 SAS

AF:

0.0112

Gnomad4 FIN

AF:

0.00339

Gnomad4 NFE

AF:

0.00137

Gnomad4 OTH

AF:

0.0270

Alfa

AF:

0.00752

Hom.:

Bravo

AF:

0.0303

Asia WGS

AF:

0.123

AC:

425

AN:

3478

EpiCase

AF:

0.00104

EpiControl

AF:

0.00107

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:2

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, criteria provided, single submitter	clinical testing	GeneDx	Feb 28, 2014	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 11, 2016

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. -

Hereditary spastic paraplegia

Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Hereditary spastic paraplegia 30

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. -

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

Invitae

Feb 01, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

Cadd

Benign

0.91

Dann

Benign

0.56

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

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