rs141441058

chr2-240722517-G-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_001244008.2(KIF1A):c.4604C>T(p.Ala1535Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,548,294 control chromosomes in the GnomAD database, including 55 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. A1535A) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0045 (2 hom., cov: 33)
  • Exomes 𝑓: 0.0075 (53 hom.)
• Consequence: KIF1A NM_001244008.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:9
• Conservation: PhyloP100: 2.66

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KIF1A
• BP4: Computational evidence support a benign effect (MetaRNN=0.0037439167).
• BP6: Variant 2-240722517-G-A is Benign according to our data. Variant chr2-240722517-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211288.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=6, Uncertain_significance=3, Benign=3}. Variant chr2-240722517-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00446 (679/152284) while in subpopulation NFE AF= 0.00849 (577/68000). AF 95% confidence interval is 0.00791. There are 2 homozygotes in gnomad4. There are 302 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 2 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KIF1A	NM_001244008.2	c.4604C>T	p.Ala1535Val	missense_variant	43/49	ENST00000498729.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KIF1A	ENST00000498729.9	c.4604C>T	p.Ala1535Val	missense_variant	43/49	5	NM_001244008.2

Frequencies

GnomAD3 genomes AF: 0.00446 AC: 679 AN: 152166 Hom.: 2 Cov.: 33

Gnomad AFR AF: 0.00142

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.000785

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00848

Gnomad OTH AF: 0.00430

GnomAD3 exomes AF: 0.00379 AC: 572 AN: 151034 Hom.: 3 AF XY: 0.00369 AC XY: 298 AN XY: 80752

Gnomad AFR exome AF: 0.00146

Gnomad AMR exome AF: 0.00102

Gnomad ASJ exome AF: 0.000477

Gnomad EAS exome AF: 0.000184

Gnomad SAS exome AF: 0.000528

Gnomad FIN exome AF: 0.000866

Gnomad NFE exome AF: 0.00856

Gnomad OTH exome AF: 0.00281

GnomAD4 exome AF: 0.00748 AC: 10446 AN: 1396010 Hom.: 53 Cov.: 32 AF XY: 0.00741 AC XY: 5104 AN XY: 688566

Gnomad4 AFR exome AF: 0.00127

Gnomad4 AMR exome AF: 0.00118

Gnomad4 ASJ exome AF: 0.000398

Gnomad4 EAS exome AF: 0.0000279

Gnomad4 SAS exome AF: 0.000379

Gnomad4 FIN exome AF: 0.00162

Gnomad4 NFE exome AF: 0.00917

Gnomad4 OTH exome AF: 0.00612

GnomAD4 genome AF: 0.00446 AC: 679 AN: 152284 Hom.: 2 Cov.: 33 AF XY: 0.00406 AC XY: 302 AN XY: 74462

Gnomad4 AFR AF: 0.00142

Gnomad4 AMR AF: 0.000784

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.00849

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00615 Hom.: 2

Bravo AF: 0.00452

TwinsUK AF: 0.00971 AC: 36

ALSPAC AF: 0.00934 AC: 36

ESP6500AA AF: 0.00196 AC: 7

ESP6500EA AF: 0.00516 AC: 40

ExAC AF: 0.00150 AC: 140

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:9

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2024	KIF1A: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Mar 19, 2019	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 07, 2023	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Feb 09, 2017	- -

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 30, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 27, 2017	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. -

Intellectual disability, autosomal dominant 9 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Oct 12, 2018

- -

Hereditary spastic paraplegia 30 Uncertain:1

Uncertain significance, 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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Hereditary spastic paraplegia Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 03, 2021

- -

Neuropathy, hereditary sensory, type 2C;C5235139:Hereditary spastic paraplegia 30;C5393830:Intellectual disability, autosomal dominant 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

KIF1A-related condition Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Nov 11, 2022

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

History of neurodevelopmental disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 18, 2017

In silico models in agreement (benign);Other strong data;Other strong data supporting benign classification -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.42
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.24	T;.;.;.;.;.;.;T;.;.;.;.;.;.
Eigen	Benign	-0.77
Eigen_PC	Benign	-0.74
FATHMM_MKL	Benign	0.39	N
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.0037	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	1.4	L;.;.;.;.;.;.;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.40	T
Polyphen		0.0	B;.;.;.;.;.;.;B;.;.;.;.;.;.
Vest4		0.16
MVP		0.47
MPC		0.43
ClinPred		0.020	T
GERP RS		3.6
Varity_R		0.063
gMVP		0.31

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: rs141441058; hg19: chr2-241661934; COSMIC: COSV57499175; COSMIC: COSV57499175;