Genetic Variant KIF1A:p.Glu917dup (chr2-240757423-A-ATCC) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3BP6BS1BS2

The NM_001244008.2(KIF1A):c.2751_2753dupGGA(p.Glu917dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.018 ( 15 hom., cov: 0)

Exomes 𝑓: 0.017 ( 62 hom. )

Consequence

KIF1A
NM_001244008.2 disruptive_inframe_insertion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:7

Conservation

PhyloP100: 1.32

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 -10 ACMG points.

BP3

Nonframeshift variant in repetitive region in NM_001244008.2

BP6

Variant 2-240757423-A-ATCC is Benign according to our data. Variant chr2-240757423-A-ATCC is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 497030.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=5, Uncertain_significance=1}.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0178 (2448/137632) while in subpopulation AFR AF= 0.0199 (761/38248). AF 95% confidence interval is 0.0187. There are 15 homozygotes in gnomad4. There are 1140 alleles in male gnomad4 subpopulation. Median coverage is 0. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 15 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KIF1A	NM_001244008.2 link	c.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	ENST00000498729.9	NP_001230937.1	Q12756-3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KIF1A	ENST00000498729.9 link	c.2751_2753dupGGA	p.Glu917dup	disruptive_inframe_insertion	Exon 27 of 49	5	NM_001244008.2	ENSP00000438388.1		Q12756-3

Frequencies

GnomAD3 genomes

AF:

0.0178

AC:

2450

AN:

137552

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0200

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0120

Gnomad ASJ

AF:

0.0163

Gnomad EAS

AF:

0.00172

Gnomad SAS

AF:

0.0181

Gnomad FIN

AF:

0.0186

Gnomad MID

AF:

0.0137

Gnomad NFE

AF:

0.0193

Gnomad OTH

AF:

0.0122

GnomAD3 exomes

AF:

0.0175

AC:

1927

AN:

110140

Hom.:

AF XY:

0.0178

AC XY:

1062

AN XY:

59702

show subpopulations

Gnomad AFR exome

AF:

0.0245

Gnomad AMR exome

AF:

0.0143

Gnomad ASJ exome

AF:

0.0120

Gnomad EAS exome

AF:

0.00143

Gnomad SAS exome

AF:

0.0190

Gnomad FIN exome

AF:

0.0185

Gnomad NFE exome

AF:

0.0201

Gnomad OTH exome

AF:

0.0294

GnomAD4 exome

AF:

0.0169

AC:

22675

AN:

1344794

Hom.:

Cov.:

AF XY:

0.0168

AC XY:

11141

AN XY:

663128

show subpopulations

Gnomad4 AFR exome

AF:

0.0213

Gnomad4 AMR exome

AF:

0.0117

Gnomad4 ASJ exome

AF:

0.0105

Gnomad4 EAS exome

AF:

0.00149

Gnomad4 SAS exome

AF:

0.0168

Gnomad4 FIN exome

AF:

0.0162

Gnomad4 NFE exome

AF:

0.0176

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0178

AC:

2448

AN:

137632

Hom.:

Cov.:

AF XY:

0.0171

AC XY:

1140

AN XY:

66654

show subpopulations

Gnomad4 AFR

AF:

0.0199

Gnomad4 AMR

AF:

0.0119

Gnomad4 ASJ

AF:

0.0163

Gnomad4 EAS

AF:

0.00172

Gnomad4 SAS

AF:

0.0179

Gnomad4 FIN

AF:

0.0186

Gnomad4 NFE

AF:

0.0193

Gnomad4 OTH

AF:

0.0121

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:7

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:1Benign:4

Apr 22, 2015

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Sep 28, 2018

Athena Diagnostics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KIF1A: BP3, BS1, BS2 -

Nov 03, 2021

Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Nov 03, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified

Benign:1

Dec 16, 2016

Eurofins Ntd Llc (ga)

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

KIF1A-related disorder

Benign:1

Jul 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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). -

KIF1A related neurological disorder

Benign:1

May 04, 2023

Molecular Genetics, Royal Melbourne Hospital

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

African population allele frequency is 1.878% (rs143816642, 761/38,136 alleles, 3 homozygotes in gnomAD v3.1). Based on the classification scheme RMH Modified ACMG/AMP Guidelines v1.6.1, this variant is classified as BENIGN. Following criteria are met: BA1 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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.

2-240757423-ATCCTCCTCCTCCTCCTCC-ATCCTCCTCCTCCTCCTCCTCC

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